CN105753793B - Fragrant formyl urea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage - Google Patents

Abstract

Fragrant formyl urea coupling quinazoline compounds or its pharmaceutically acceptable salt, R shown in a kind of formula (I) of present invention offer₂Or R₃One of for group shown in formula (II)；

Description

Aroylurea-coupled quinazoline compounds, preparation method thereof, pharmaceutical composition and drug use

technical field

The invention relates to an aromatic formyl urea coupled quinazoline compound, which has protein tyrosine kinase inhibitory effect and tubulin inhibitory effect, and is suitable for treating tumor-related diseases. The present invention also relates to a preparation method of an aroylurea-coupled quinazoline compound, a preparation method of an intermediate of this type of compound, its application, especially the use of this type of compound as an active ingredient in the preparation of drugs for the treatment of tumor-related diseases The use of and the pharmaceutical composition containing it.

Background technique

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein composed of a single polypeptide chain, which is activated after binding to extracellular growth factor (EGF), which can selectively make receptors containing tyrosine residues body protein phosphorylation. This tyrosine phosphorylation is related to many cell regulatory processes, such as the activation of T cells and B cells, mitosis, differentiation and development, response to external stimuli, cell survival and growth regulation, etc. (F.Al-Obeidi et al. Al, Peptide Science 47 (1998), 197 and T. Hunter, Cell 88 (1997), 333). Studies have shown that when the tyrosine protein kinase is overexpressed, the growth regulation of the cell is out of control, and it is always in a state of proliferation, and then develops into a malignant tumor (R. Patarca, Critical Reviews in Oncogenesis 7 (1996), 343). Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) are the earliest targeted anti-tumor drugs used clinically for the treatment of non-small cell lung cancer (NSCLC). - The status of TKIs in the first-line treatment of EGFR-mutant NSCLC, with a median progression-free period of 9 to 13 months. However, almost all patients treated with EGFR-TKIs inevitably develop drug resistance eventually, and the primary and acquired drug resistance of NSCLC patients to EGFR-TKIs limits its clinical application. Primary drug resistance refers to drug resistance when EGFR-TKIs are used for the first time, about 60% of NSCLC patients have primary drug resistance to TKIs, and nearly 30% of NSCLC patients with TKIs-sensitive mutations in EGFR gene will develop drug resistance Primary drug resistance, primary drug resistance may make some NSCLC patients have to change the treatment plan of EGFR-TKIs. Acquired drug resistance means that EGFR-TKIs can play a good role in NSCLC patients, but most patients will develop drug resistance within 6 to 12 months of treatment. For example, patients who take gefitinib with significant curative effect, even if they are highly sensitive to EGFR-TKIs, usually develop drug resistance after about one year of treatment, and seriously affect the treatment effect. Current studies have found that the main drug resistance mechanisms of EGFR-TKIs include: T790M mutation, C-MET amplification, K-RAS mutation, PTEN expression inactivation, and the influence of EGFR-independent RPTKs signal transduction pathways (such as VEGFR and PDGFR ) and changes in the tumor microenvironment, among which T790M mutation is the most common, and about 50% of NSCLC patients have T790M mutation.

Since the molecular structure of the kinase receptor target is mutatable, longitudinal analysis of the whole process of TKIs drug development reveals that designing a drug for a certain receptor model structure enables it to maintain targeting in the long-term interaction with tumor cells , and can continuously and effectively inhibit tumor cell proliferation and solve the problem of TKIs drug resistance has always been an extremely challenging task. The development of anti-tumor drugs with dual anti-tumor mechanisms can effectively avoid the risk of drug resistance caused by single-target TKIs due to receptor structural mutations, and has high therapeutic efficiency, good safety, and more significant tumor inhibitory effects. Microtubules are the main components of the cytoskeleton and play an important role in maintaining cell shape, cell division, signal transduction and other processes. Due to the important role of microtubules in the process of cell division, tubulin has become one of the important targets for research and development of new anticancer drugs, and tubulin inhibitors acting on the microtubule system have also become a class of effective anticancer agents. tumor drugs. The mechanism of action of such inhibitors is to interfere with the mitotic process of cells by inhibiting the polymerization of tubulin or promoting the polymerization of tubulin, thereby exerting an anti-tumor effect. Therefore, it is of great significance to develop new compounds with protein kinase inhibitory effect and tubulin inhibitory effect.

Contents of the invention

One object of the present invention is to provide an araformylurea-coupled quinazoline compound or a pharmaceutically acceptable salt thereof, which can be used for treating tumor-related diseases.

Another object of the present invention is to provide a method for preparing the above-mentioned aroylurea-coupled quinazoline compound or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the above-mentioned intermediates of araformylurea-coupled quinazoline compounds.

Another object of the present invention is to provide a pharmaceutical composition.

Another object of the present invention is to provide the use of the above-mentioned aroylurea-coupled quinazoline compound or a pharmaceutically acceptable salt thereof in the preparation of drugs related to tumor-related diseases.

In order to achieve the above object, the technical scheme adopted in the present invention is as follows:

In one aspect, the present invention provides an aroylurea-coupled quinazoline compound represented by formula (I) or a pharmaceutically acceptable salt thereof;

Wherein, R ₁ is H; Br, Cl or F; -CH ₃ , -CH ₂ -CH ₃ , -CH ₂ (CH ₃ ) ₂ or -CF ₃ ; -O-CH ₃ , -O-CH ₂ -CH ₃ or -O-CH ₂ (CH ₃ ) ₂ ; -C≡CH or -C≡N;

n ₁ is 1, 2, 3, 4 or 5;

One of R ₂ or R ₃ is a group shown in formula (II);

Wherein, R ₄ is H; Br, Cl or F; -CH ₃ , -CH ₂ -CH ₃ , -CH ₂ (CH ₃ ) ₂ or -CF ₃ ; -O-CH ₃ , -O-CH ₂ -CH ₃ or -O-CH ₂ (CH ₃ ) ₂ ; -NH ₂ ; or -NO ₂ ;

n ₂ is 1, 2, 3, 4 or 5;

The other one of R ₂ or R ₃ is H, -O-CH ₃ , -O-CH ₂ -CH ₃ , -O-CH ₂ (CH ₃ ) ₂ , or

Preferably, the aroylurea-coupled quinazoline compounds shown in the formula (I) are selected from the following compounds:

1-Benzoyl-3-(4-anilinoquinazolin-7-yl)urea

1-Benzoyl-3-[4-(2-methylanilino)quinazolin-7-yl]urea

1-Benzoyl-3-[4-(3-methylanilino)quinazolin-7-yl]urea

1-Benzoyl-3-[4-(4-methylanilino)quinazolin-7-yl]urea

1-Benzoyl-3-[4-(2-chloroanilino)quinazolin-7-yl]urea

1-Benzoyl-3-[4-(4-fluoroanilino)quinazolin-7-yl]urea

1-Benzoyl-3-[4-(3-isopropylanilino)quinazolin-7-yl]urea

1-Benzoyl-3-[4-(4-methoxyanilino)quinazolin-7-yl]urea

1-Benzoyl-3-[4-(4-bromo-3-fluoroanilino)quinazolin-7-yl]urea

1-Benzoyl-3-[4-(2,4-difluoroanilino)quinazolin-7-yl]urea

1-Benzoyl-3-[4-(2,4,6-trimethylanilino)quinazolin-7-yl]urea

1-benzoyl-3-[4-(2,3-dimethylanilino)quinazolin-7-yl]urea

1-Benzoyl-3-[4-(3-trifluoromethylanilino)quinazolin-7-yl]urea

1-(2-methylbenzoyl)-3-[4-(2-chloroanilino)quinazolin-7-yl]urea

1-(4-methylbenzoyl)-3-[4-(3-methylanilino)quinazolin-7-yl]urea

1-(4-methylbenzoyl)-3-[4-(3-isopropylanilino)quinazolin-7-yl]urea

1-(4-Chlorobenzoyl)-3-[4-(3-isopropylanilino)quinazolin-7-yl]urea

1-(2,6-Difluorobenzoyl)-3-[4-anilinoquinazolin-7-yl]urea

1-(2,6-Difluorobenzoyl)-3-[4-(2-methylanilino)quinazolin-7-yl]urea

1-(2,6-Difluorobenzoyl)-3-[4-(2-chloroanilino)quinazolin-7-yl]urea

1-(2,6-difluorobenzoyl)-3-[4-(2,3-dimethylanilino)quinazolin-7-yl]urea

1-(2,6-difluorobenzoyl)-3-[4-(2,4-difluoroanilino)quinazolin-7-yl]urea

1-(2,6-difluorobenzoyl)-3-[4-(3-chloro-4-fluoroanilino)quinazolin-7-yl]urea

1-(2,6-Difluorobenzoyl)-3-[4-(4-bromo-3-fluoroanilino)quinazolin-7-yl]urea

1-(2,6-Difluorobenzoyl)-3-[4-(3-trifluoromethylanilino)quinazolin-7-yl]urea

1-Benzoyl-3-(4-anilinoquinazolin-6-yl)urea

1-Benzoyl-3-[4-(4-fluoroanilino)quinazolin-6-yl]urea

1-Benzoyl-3-[4-(2-methylanilino)quinazolin-6-yl]urea

1-Benzoyl-3-[4-(4-methylanilino)quinazolin-6-yl]urea

1-Benzoyl-3-[4-(3-cyanoanilino)quinazolin-6-yl]urea

1-Benzoyl-3-[4-(3-bromoanilino)quinazolin-6-yl]urea

1-Benzoyl-3-[4-(3-chloro-4-fluoroanilino)quinazolin-6-yl]urea

1-Benzoyl-3-(7-methoxy-4-anilinoquinazolin-6-yl)-urea

1-Benzoyl-3-[7-methoxy-4-(4-chloro-3-trifluoromethylanilino)quinazolin-6-yl]-urea

1-Benzoyl-3-[7-methoxy-4-(4-bromoanilino)quinazolin-6-yl]-urea

1-Benzoyl-3-[7-methoxy-4-(3-bromoanilino)quinazolin-6-yl]-urea

1-Benzoyl-3-[7-(4-methylpiperazin-1-yl)-4-(2-methylanilino)quinazolin-6-yl]urea

1-Benzoyl-3-[7-(4-methylpiperazin-1-yl)-4-(3-bromoanilino)quinazolin-6-yl]urea

1-Benzoyl-3-[7-(morpholin-4-yl)-4-anilinoquinazolin-6-yl]urea

1-Benzoyl-3-[7-(morpholin-4-yl)-4-(2-fluoro-4-bromoanilino)quinazolin-6-yl]urea

1-Benzoyl-3-[7-(morpholin-4-yl)-4-(3-chloro-4-fluoroanilino)quinazolin-6-yl]urea

1-benzoyl-3-(6-methoxy-4-anilinoquinazolin-7-yl)urea

1-Benzoyl-3-[6-(4-methylpiperazin-1-yl)-4-anilinoquinazolin-7-yl]urea

1-Benzoyl-3-[7-(4-methylpiperazin-1-yl)-4-(2-fluoro-4-bromoanilino)quinazolin-6-yl]urea

1-Benzoyl-3-[7-(4-methylpiperazin-1-yl)-4-(2-methyl-4-methoxyanilino)quinazolin-6-yl]urea

1-benzoyl-3-[7-(4-methylpiperazin-1-yl)-4-(4-chloro-3-trifluoromethylanilino)quinazolin-6-yl]urea or

1-benzoyl-3-[6-(morpholin-4-yl)-4-anilinoquinazolin-7-yl]urea; or salts of these compounds.

Preferably, the pharmaceutically acceptable salt includes but not limited to hydrochloride, hydrobromide, sulfate, hemisulfate, phosphate, amino acid salt or carboxylate.

On the other hand, the present invention provides a method for preparing the aroylurea-coupled quinazoline compound shown in the above formula (I) or a pharmaceutically acceptable salt thereof, which comprises adding the compound shown in the formula (VII) The compound shown in the compound and the formula (VIII) is in an organic solvent to generate a compound shown in the formula (I);

One of R ₇ or R ₈ is NH ₂ ;

The other one of R ₇ or R ₈ is H, -O-CH ₃ , -O-CH ₂ -CH ₃ , -O-CH ₂ (CH ₃ ) ₂ , or

The definitions of R ₄ and n ₂ are the same as the definitions of R ₄ and n ₂ in formula (I).

Preferably, the above-mentioned organic solvent is selected from acetonitrile or anhydrous tetrahydrofuran.

Preferably, the method further comprises: reacting the compound represented by formula (I) with an acid or base in an organic solvent to generate a compound represented by formula (X);

Among them, M is hydrochloric acid, hydrobromic acid, sulfuric acid, hemisulfuric acid, phosphoric acid, amino acid, other carboxylic acids, preferably hydrochloric acid; the definitions of R ₁ , n ₁ , R ₂ , and R ₃ are the same as R ₁ , n ₁ in formula (I). , R ₂ and R ₃ have the same definition, preferably, the organic solvent is absolute ethanol or dichloromethane.

In another aspect, the present invention provides a method for preparing the intermediate of the compound shown in the above formula (I), wherein the intermediate is benzoyl isocyanate, the method comprising:

Reaction of the compound shown in formula (IX) with oxalyl chloride in an organic solvent to obtain the corresponding benzoyl isocyanate intermediate of the compound of formula (IX),

Wherein, the definitions of R ₄ and n ₂ are the same as the definitions of R ₄ and n ₂ in formula (I).

Preferably, the above-mentioned method specifically comprises: under the ice-water bath cooling condition, the 1,2-dichloroethane solution of the compound represented by formula (IX) is added dropwise in the 1,2-dichloroethane of oxalyl chloride, Control the rate of addition, preferably 2 drops/second. After the dropwise addition, heat to 50°C and stir for 17h, place it at room temperature, evaporate the solvent to obtain an oily substance, and then obtain the corresponding compound shown in formula (IX) after fractional distillation under reduced pressure. Benzoyl isocyanate intermediates.

In another aspect, the present invention provides a method for preparing the compound shown in the intermediate formula (VII) of the compound shown in the above formula (I), the method comprising the steps of:

Step a: the compound represented by formula (III) is reacted with a catalyst in an organic solvent to generate a compound represented by formula (IV);

Wherein, one of R ₅ or R ₆ is NO ₂ ;

The other one of R ₅ or R ₆ is H, -O-CH ₃ , -O-CH ₂ -CH ₃ , -O-CH ₂ (CH ₃ ) ₂ , or

Step b: the compound represented by formula (IV) reacts with the compound represented by formula (V) in an organic solvent to generate the compound represented by formula (VI);

Wherein, the definitions of R ₁ and n ₁ are the same as the definitions of R ₁ and n ₁ in formula (I);

Step c: react the compound represented by formula (VI) with a reducing agent in an organic solvent, preferably under reflux for 1 h, to generate the compound represented by formula (VII).

Preferably, the organic solvent in the step a is thionyl chloride, and the catalyst is dimethylformamide (DMF);

Preferably, the organic solvent in the step b is isopropanol, anhydrous acetonitrile or anhydrous tetrahydrofuran;

Preferably, the organic solvent in step c is ethyl acetate or absolute ethanol; the reducing agent is preferably one or more of stannous chloride, hydrazine hydrate, palladium carbon or Raney nickel.

In another aspect, the present invention provides a pharmaceutical composition, which comprises the araformylurea-coupled quinazoline compound and/or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, excipient or diluent.

Compositions comprising at least one compound and/or at least one pharmaceutically acceptable salt according to the invention can be administered in various known ways, for example orally, parenterally, by inhalation spray or via Implanted depot administration. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention can be administered alone or in combination with other antitumor drugs. The animals to be treated include mammals, reptiles, crustaceans, amphibians, fish, and poultry. The present invention particularly refers to humans.

Oral compositions can be in any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. Examples of commonly used pharmaceutically acceptable carriers and pharmaceutically acceptable excipients and diluents include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, fillers, emulsifying agents, Agents, or taste modifiers, specifically including but not limited to magnesium stearate, talc, silicon dioxide, dry starch, sodium carboxycellulose, sodium starch glycolate, hydroxypropyl cellulose and crospovidone Wait.

Sterile injectable compositions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable semi-finished product may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. Among the pharmaceutically acceptable carriers and solvents that may be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed oil is often used as a solvent or suspending medium. Fatty acids, such as oleic acid and its glyceride derivatives are useful in injectable preparations, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.

Compositions for inhalation can be prepared according to well-known techniques in the field of pharmaceutical preparations, and can be prepared by using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons and/or other solubilizing or dispersing agents known in the art. Prepared as a solution in saline.

Topical compositions may be formulated as oils, creams, lotions, ointments, and the like. Suitable carriers for the composition include vegetable or mineral oil, white petrolatum, branched chain fats or oils, animal fats and high molecular weight alcohols. A pharmaceutically acceptable carrier is one in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants, and antioxidants, as well as color or fragrance-imparting substances, may also be included, if desired.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient.

The selected dosage level will depend on a variety of factors, including the activity of the particular compound of the invention employed, or its ester, salt or amide, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of treatment, Other drugs, compounds and/or materials used in combination with the particular compound used, the age, sex, weight, condition, general health and previous medical history of the patient being treated and similar factors well known in the medical art.

Preferably, the pharmaceutical composition of the present invention may further contain other active substances other than the above-mentioned aroylurea-coupled quinazoline compounds and/or pharmaceutically acceptable salts thereof.

In yet another aspect, the present invention provides any one of the above-mentioned aroylurea-coupled quinazoline compounds and/or pharmaceutically acceptable salts thereof in the preparation of therapeutic and protein tyrosine kinase inhibitory activity and/or microtubule Use in medicine for diseases associated with protein inhibitory activity.

In the last aspect, the present invention provides the use of any one of the above-mentioned aroylurea-coupled quinazoline compounds or pharmaceutically acceptable salts thereof in the preparation of drugs related to tumor-related diseases.

Wherein, the tumor-related diseases are malignant tumors, including but not limited to: lung cancer, preferably non-small cell lung cancer; pancreatic cancer; phosphorous epithelial cancer; medullary thyroid cancer; head and neck cancer; esophageal cancer; gastric cancer; or Gynecological cancers are preferably bladder cancer and breast cancer.

The present invention is through the research (L.Hennequin, Journal of Medicinal Chemistry (1999), 42 (26), 5369-5389) to the structure-activity relationship of 4-anilinoquinazoline drugs, according to the 4-anilino group in the prior art The understanding of the structure-activity relationship of quinazoline drugs, combined with the study of the structure-activity relationship of drug molecules that inhibit tubulin, using the "molecular hybridization" method, the basic skeleton structure of classic small molecule EGFR tyrosine kinase inhibitors 4-anilinoquinazoline is fused with the active structure of small molecule tubulin inhibitor (benzoyl urea) to form a new 4-protein that has both the targeted inhibition of EGFR tyrosine kinase and the inhibition of tubulin polymerization - The drug molecular entity of anilinoaroyl urea coupling quinazoline compound structure (see scheme 1 for the binding mode), based on the above concept, after research and creation work, the overall technical solution of the present invention is formed.

The aromatic formylurea-coupled quinazoline compounds provided by the present invention have been found to have obvious pharmacological activity in some structures. The aromatic formyl urea-coupled quinazoline compound or the pharmaceutically acceptable salt thereof of the present invention can effectively treat tumor-related diseases. It is beneficial to improve the anti-tumor activity of the target object, and will also be beneficial to increase the anti-drug resistance of the target object molecule.

Process 1

Detailed ways

The present invention will be described below with reference to specific examples. Those skilled in the art can understand that these examples are only used to illustrate the present invention and do not limit the scope of the present invention in any way.

The experimental methods in the following examples are conventional methods unless otherwise specified. The medicines, reagents, etc. used in the following examples are all commercially available products unless otherwise specified.

The final products in the examples of the present invention were determined by mass spectrometry (ESI-MS) and ¹ H-NMR (500 MHz in dimethyl sulfoxide (DMSO)).

Example 1 Synthesis of 1 -benzoyl-3-(4-anilinoquinazolin-7-yl)urea (compound 1)

The synthetic route and method of compound 1 are as follows:

Step 1: Preparation of 7-nitro-3H-quinazolin-4-one

Add 2-amino-4-nitrobenzoic acid (7.28g, 40.0mmol) and ammonium formate (3.78g, 60.0mmol) into 100mL formamide, heat to 150°C, keep the reaction for 16h, cool to room temperature, and precipitate a solid , filtered, washed with isopropanol, and dried to obtain 6.62 g of brown needle-like solid 7-nitro-3H-quinazolin-4-one with a yield of 86.6%.

Step 2: Preparation of 7-nitro-4-anilinoquinazoline

7-Nitro-3H-quinazolin-4-one (2.25g, 11.8mmol) was added to _23mL SOCl solution, then 0.2mL DMF was added, refluxed and stirred for 1h, the solution gradually became brown and clear, and the reaction was stopped. After cooling to room temperature, excess SOCl ₂ was distilled off to obtain 7-nitro-4-chloroquinazoline as a yellow solid. The obtained yellow solid was crushed, 10 mL of petroleum ether was added, the petroleum ether was distilled off under reduced pressure, and the operation of adding petroleum ether was repeated twice to remove residual SOCl ₂ to obtain a yellow solid. Add aniline (1.31g, 14.1mmol) and isopropanol 37mL to the above yellow solid without purification, and stir at reflux for 1.5h, a solid precipitates, cool to room temperature, filter, wash with isopropanol, and dry to give a yellow solid 7 -Nitro-4-anilinoquinazoline 1.87 g, yield 59.7%.

Step 3: Preparation of 7-amino-4-anilinoquinazoline

7-nitro-4-anilinoquinazoline (1.31g, 4.9mmol), stannous chloride dihydrate (4.42g, 19.6mmol) and ethyl acetate 49mL were mixed and refluxed for 1h. The reaction solution becomes clear first, and then precipitates appear. After the reaction is completed, place it at room temperature and filter. The resulting precipitate is washed with ethyl acetate, combined with the ethyl acetate solution, adjusted to neutrality with saturated sodium bicarbonate solution, and the ethyl acetate layer is separated. , washed with 10 mL of water, dried over anhydrous Na ₂ SO ₄ , concentrated to dryness under reduced pressure, and dried to obtain 0.95 g of 7-amino-4-anilinoquinazoline as a yellow solid with a yield of 81.1%.

Step 4: Preparation of Benzoyl Isocyanate

Under cooling in an ice-water bath, a mixed solution of benzoylurea (0.73 g, 6.0 mmol) in 1,2-dichloroethane (7 mL) was slowly added dropwise to oxalyl chloride (0.94 g, 7.5 mmol) and dry 1, In a solution of 2-dichloroethane (7mL), control the rate of addition (2 drops/second). After the addition is complete, stir at room temperature for 1h, raise the temperature to 50°C and keep stirring for 17h, place it at room temperature, and evaporate the solvent to obtain an oil 0.70 g of colorless liquid phenyl isocyanate was obtained through fractional distillation under reduced pressure, and the yield was 79.3%.

Step 5: Preparation of 1-benzoyl-3-(4-anilinoquinazolin-7-yl)urea

Benzoyl isocyanate (0.32g, 2.2mmol) was added to 20mL acetonitrile, under stirring at room temperature, 7-amino-4-anilinoquinazoline (0.47g, 2.0mmol) was added in batches, stirred at room temperature for 3h, and filtered to obtain The solid was washed with acetonitrile, dried, and recrystallized from a mixture of dichloromethane and methanol to obtain 0.62 g of light yellow solid 1-benzoyl-3-(4-anilinoquinazolin-7-yl)urea (compound 1) , and the yield was 80.9%.

Example 2 Synthesis of 1-benzoyl-3-[4-(4-methylanilino)quinazolin-7-yl]urea (compound 2)

The preparation method is the same as in Example 1, the difference is that the aniline added in Step 2 in Example 1 is replaced by 4-methylaniline in an equimolar amount, and the reactant 7-nitro-4-anilino in Step 3 is Quinazoline is replaced with 7-nitro-4-(4-methylanilino) quinazoline of equimolar amount, and the reactant 7-amino-4-anilinoquinazoline in step 5 is replaced with equimolar amount of 7-amino-4-(4-methylanilino)quinazoline, the total yield was 26.8%.

Example 3 Synthesis of 1-benzoyl-3-[4-(3-methylanilino)quinazolin-7-yl]urea (compound 3)

The preparation method is the same as in Example 1, except that the aniline added in Step 2 of Example 1 is replaced by 3-methylaniline in an equimolar amount, and the reactant 7-nitro-4-anilinoquinoline in Step 3 is The oxazoline is replaced with 7-nitro-4-(3-methylanilino) quinazoline of equimolar amount, and the reactant 7-amino-4-anilino quinazoline in step 5 is replaced with equimolar amount The total yield of 7-amino-4-(3-methylanilino)quinazoline was 23.7%.

Example 4 Synthesis of 1-benzoyl-3-[4-(4-methoxyanilino)quinazolin-7-yl]urea (compound 4)

The preparation method is the same as in Example 1, except that the aniline added in Step 2 of Example 1 is replaced by an equimolar amount of 4-methoxyaniline, and the reactant 7-nitro-4-anilino in Step 3 is Quinazoline is replaced with 7-nitro-4-(4-methoxyanilino) quinazoline of equimolar amount, the reactant 7-amino-4-anilino quinazoline in step 5 is replaced with etc. The molar amount of 7-amino-4-(3-methoxyanilino)quinazoline has a total yield of 24.4%.

Example 5 Synthesis of 1-benzoyl-3-[4-(2-fluoro-4-bromoanilino)quinazolin-7-yl]urea (compound 5)

The preparation method is the same as in Example 1, except that the aniline added in Step 2 of Example 1 is replaced by an equimolar amount of 2-fluoro-4-bromoaniline, and the reactant 7-nitro-4- Anilinoquinazoline is replaced with 7-nitro-4-(2-fluoro-4-bromoanilino) quinazoline of equimolar amount, the reactant 7-amino-4-anilinoquinazole in step 5 The morphine was replaced by an equimolar amount of 7-amino-4-(2-fluoro-4-bromoanilino)quinazoline with a total yield of 18.1%.

Example 6 Synthesis of 1-benzoyl-3-[4-(3-isopropylanilino)quinazolin-7-yl]urea (compound 6)

The preparation method is the same as in Example 1, the difference is that the aniline added in Step 2 of Example 1 is replaced by an equimolar amount of 3-isopropylaniline, and the reactant 7-nitro-4-anilino in Step 3 is Quinazoline is replaced with 7-nitro-4-(3-isopropylanilino) quinazoline of equimolar amount, the reactant 7-amino-4-anilino quinazoline in step 5 is replaced with etc. The molar amount of 7-amino-4-(3-isopropylanilino)quinazoline has a total yield of 28.8%.

Example 7 Synthesis of 1-benzoyl-3-[4-(2-chloroanilino)quinazolin-7-yl]urea (compound 7)

The preparation method is the same as in Example 1, the difference is that the aniline added in Step 2 of Example 1 is replaced by 2-chloroaniline in an equimolar amount, and the reactant 7-nitro-4-anilinoquinazole in Step 3 Phylline is replaced with 7-nitro-4-(2-chloroanilino) quinazoline of equimolar quantity, and the reactant 7-amino-4-anilininoquinazoline in step 5 is replaced with equimolar quantity of 7 -Amino-4-(2-chloro-anilino)quinazoline, the total yield is 29.2%.

Example 8 Synthesis of 1-benzoyl-3-[4-(2,4,6-trimethylanilino)quinazolin-7-yl]urea (compound 8)

The preparation method is the same as in Example 1, except that the aniline added in Step 2 of Example 1 is replaced by an equimolar amount of 2,4,6-trimethylaniline, and the reactant 7-nitro- 4-anilinoquinazoline is replaced with equimolar 7-nitro-4-(2,4,6-trimethylanilino) quinazoline, reactant 7-amino-4-in step 5 The anilinoquinazoline was replaced by an equimolar amount of 7-amino-4-(2,4,6-trimethylanilino)quinazoline, and the total yield was 20.9%.

Example 9 Synthesis of 1-benzoyl-3-[4-(2,3-dimethylanilino)quinazolin-7-yl]urea (compound 9)

The preparation method is the same as in Example 1, except that the aniline added in Step 2 of Example 1 is replaced by 2,3-dimethylaniline in an equimolar amount, and the reactant 7-nitro-4- Anilinoquinazoline is replaced with 7-nitro-4-(2,3-dimethylanilino) quinazoline in equimolar amounts, the reactant 7-amino-4-anilinoquinazole in step 5 The morphine was replaced by an equimolar amount of 7-amino-4-(2,3-dimethylanilino)quinazoline, and the total yield was 25.0%.

Example 10 Synthesis of 1-(2-methylbenzoyl)-3-[4-(2-chloroanilino)ylquinazolin-7-yl]urea (compound 10)

The preparation of intermediate 7-amino-4-(2-chloroanilino)quinazoline is the same as the experimental operation of step 1-3 in Example 7.

The preparation of the intermediate 2-methylbenzoyl isocyanate is the same as the experimental operation of step 4 in Example 1, the only difference being that the reactant benzamide is replaced by an equimolar amount of 2-methylbenzamide.

The preparation of 1-(2-methylbenzoyl)-3-[4-(2-chloroanilino)quinazolin-7-ylurea] is the same as the experimental operation of step 5 in Example 7, the only difference is In this step, the reactant benzoyl isocyanate was replaced with an equimolar amount of 2-methylbenzoyl isocyanate, and the total yield was 28.3%.

Example 11 Synthesis of 1-benzoyl-3-[4-(2,4-difluoroanilino)quinazolin-7-yl]urea (compound 11)

The preparation method is the same as in Example 1, the difference is that the aniline in step 2 is replaced by equimolar 2,4-difluoroaniline, and the reactant 7-nitro-4-anilinoquinazoline in step 3 is replaced Become the 7-nitro-4-(2,4-difluoroanilino) quinazoline of equimolar amount, replace the reactant 7-amino-4-anilinoquinazoline in step 5 with equimolar amount 7-Amino-4-(2,4-difluoroanilino)quinazoline, the total yield is 34.0%.

Example 12 Synthesis of 1-(2,4-difluorobenzoyl)-3-(4-anilinoquinazolin-7-yl)urea (compound 12)

The preparation method is the same as in Example 1, except that the reactant benzamide in step 4 is replaced with equimolar 2,4-difluorobenzamide, and the reactant benzoyl isocyanate in step 5 is replaced with equimolar amount of 2,4-difluorobenzoyl isocyanate, the total yield was 21.2%.

Example 13 Synthesis of 1-(4-chlorobenzoyl)-3-[4-(3-isopropylanilino)ylquinazolin-7-yl]urea (compound 13)

The preparation method is the same as in Example 1, and the difference is that the reactant benzamide in step 4 is replaced with 4-chlorobenzamide in equimolar quantities, and the reactant benzoyl isocyanate in step 5 is replaced with 4-chlorobenzamide in equimolar quantities. - Chlorobenzoyl isocyanate, the total yield is 22.4%.

Example 14 Synthesis of 1-(4-methylbenzoyl)-3-[4-(3-isopropylanilino)quinazolin-7-yl]urea (compound 14)

The preparation method is the same as in Example 1, except that the reactant benzamide in step 4 is replaced with 4-methylbenzamide in equimolar amounts, and the reactant benzoyl isocyanate in step 5 is replaced with equimolar amounts of 4-Methylbenzoyl isocyanate, the total yield is 22.8%.

Example 15 Synthesis of 1-(4-methylbenzoyl)-3-[4-(3-methylanilino)quinazolin-7-yl]urea (compound 15)

The preparation of intermediate 7-amino-4-(3-methylanilino)quinazoline is the same as step 1-3 in Example 3.

Preparation of intermediate 4-methylbenzoyl isocyanate according to step 4 in Example 14.

The preparation of 1-(4-methylbenzoyl)-3-[4-(3-methylanilino)quinazolin-7-yl]urea refers to the experimental operation of step 5 in Example 3, the only difference In order to replace the reactant benzoyl isocyanate in this step with an equimolar amount of 4-methylbenzoyl isocyanate, the total yield was 20.2%.

Example 16 Synthesis of 1-benzoyl-3-[4-(4-fluoroanilino)quinazolin-7-yl]urea (compound 16)

The preparation method is the same as in Example 1, the difference is that the aniline in step 2 is replaced by equimolar 4-fluoroaniline, and the reactant 7-nitro-4-anilinoquinazoline in step 3 is replaced by equimolar amount of 7-nitro-4-(4-fluoroanilino) quinazoline, the reactant 7-amino-4-anilinoquinazoline in step 5 is replaced by equimolar amounts of 7-amino-4- (4-Fluoroanilino)quinazoline, the total yield is 26.3%.

Example 17 Synthesis of 1-benzoyl-3-[4-(2-methylanilino)quinazolin-7-yl]urea (compound 17)

The preparation method is the same as in Example 1, except that the aniline in step 2 is replaced by 2-methylaniline in an equimolar amount, and the reactant 7-nitro-4-anilinoquinazoline in step 3 is replaced by The 7-nitro-4-(2-methylanilino) quinazoline of molar weight, the reactant 7-amino-4-anilino quinazoline in step 5 is replaced with the 7-amino- 4-(2-Methylanilino)quinazoline, the total yield is 28.9%.

Example 18 The synthesis and preparation method of 1-benzoyl-3-[4-(3-trifluoromethylanilino)quinazolin-7-yl]urea (compound 18) is the same as in Example 1, except that The aniline in step 2 is replaced by 3-trifluoromethylaniline in equimolar amounts, and the reactant 7-nitro-4-anilinoquinazoline in step 3 is replaced by 7-nitro-4 in equimolar amounts -(3-trifluoromethylanilino) quinazoline, the reactant 7-amino-4-anilinoquinazoline in step 5 is replaced by 7-amino-4-(3-trifluoro methylanilino) quinazoline, the total yield is 32.8%.

Example 19 Synthesis of 1-(2,4-difluorobenzoyl)-3-[4-(2-methylanilino)quinazolin-7-yl]urea (Compound 19)

The preparation of the intermediate 7-amino-4-(2-methylanilino)quinazoline is the same as Step 1-3 of Example 17.

The synthesis of the intermediate 2,4-difluorobenzoyl isocyanate is the same as that of Step 4 of Example 12. The preparation of 1-(2,4-difluorobenzoyl)-3-[4-(4-methylanilino)quinazolin-7-yl]urea is the same as the experimental operation of step 5 of Example 17, the only difference The place is to replace the reactant benzoyl isocyanate in this step with an equimolar amount of 2,4-difluorobenzoyl isocyanate, and the total yield is 22.2%.

Example 20 Synthesis of 1-(2,4-difluorobenzoyl)-3-[4-(2,3-dimethylanilino)quinazolin-7-yl]urea (compound 20)

The preparation of the intermediate 7-amino-4-(2,3-dimethylanilino)quinazoline is the same as the experimental operation of steps 1-3 of Example 9.

The synthesis of the intermediate 2,4-difluorobenzoyl isocyanate is the same as that of Step 4 of Example 12.

The preparation of 1-benzoyl-3-[4-(2,3-dimethylanilino) quinazoline-7-yl] urea is the same as the experimental operation of step 5 in Example 9, the only difference is that this The reactant benzoyl isocyanate in the step is replaced by 2,4-difluorobenzoyl isocyanate in an equimolar amount, and the total yield is 32.1%.

Example 21 Synthesis of 1-(2,4-difluorobenzoyl)-3-[4-(2,4-difluoroanilino)quinazolin-7-yl]urea (Compound 21)

The preparation of the intermediate 7-amino-4-(2,3-dimethylanilino)quinazoline is the same as that of Step 1-3 of Example 11.

The synthesis of the intermediate 2,4-difluorobenzoyl isocyanate is the same as that of Step 4 of Example 12.

Step 5: Preparation of 1-(2,4-difluorobenzoyl)-3-[4-(2,4-difluoroanilino)quinazolin-7-yl]urea

Refer to the experimental operation of step 5 in Example 11, the only difference is that the reactant benzoyl isocyanate in this step is replaced by an equimolar amount of 2,4-difluorobenzoyl isocyanate, and the total yield is 23.5%.

Example 22 Synthesis of 1-(2,4-difluorobenzoyl)-3-[4-(2-chloroanilino)quinazolin-7-yl]urea (Compound 22)

The preparation of the intermediate 7-amino-4-(2-chloroanilino)quinazoline is the same as Step 1-3 of Example 7.

The synthesis of the intermediate 2,4-difluorobenzoyl isocyanate is the same as that of Step 4 of Example 12.

The preparation of 1-(2,4-difluorobenzoyl)-3-[4-(2-chloroanilino)quinazolin-7-yl]urea is the same as the experimental operation of step 5 in Example 7, the only difference The place is to replace the reactant benzoyl isocyanate in this step with an equimolar amount of 2,4-difluorobenzoyl isocyanate, and the total yield is 34.1%.

Example 23 Synthesis of 1-(2,4-difluorobenzoyl)-3-[4-(3-trifluoromethylanilino)quinazolin-7-yl]urea (Compound 23)

The preparation method of the intermediate 7-amino-4-(3-trifluoromethylanilino)quinazoline is the same as Step 1-3 of Example 18.

The synthesis of the intermediate 2,4-difluorobenzoyl isocyanate is the same as that of Step 4 of Example 12.

The preparation of 1-(2,4-difluorobenzoyl)-3-[4-(3-trifluoromethylanilino)quinazolin-7-yl]urea is the same as the experimental operation of step 5 in Example 18, The only difference is that the reactant benzoyl isocyanate in this step is replaced by an equimolar amount of 2,4-difluorobenzoyl isocyanate, and the total yield is 18.8%.

Example 24 Synthesis of 1-(2,4-difluorobenzoyl)-3-[4-(2-fluoro-4-bromoanilino)quinazolin-7-yl]urea (Compound 24)

The preparation of the intermediate 7-amino-4-(2-fluoro-4-bromoanilino)quinazoline is the same as steps 1-3 in Example 5.

The synthesis of the intermediate 2,4-difluorobenzoyl isocyanate is the same as that of Step 4 of Example 12.

The preparation of 1-(2,4-difluorobenzoyl)-3-[4-(2-fluoro-4-bromoanilino)quinazolin-7-yl]urea is the same as the experimental operation of step 5 in Example 5 , the only difference is that the reactant benzoyl isocyanate in this step is replaced by an equimolar amount of 2,4-difluorobenzoyl isocyanate, and the total yield is 16.5%.

Example 25 1-(2,4-difluorobenzoyl)-3-[4-(3-chloro-4-fluoroanilino)quinazolin-7-yl]urea (Compound 25)

For Step 1, refer to the experimental operation of Step 1 in Example 1.

Step 2: Preparation of 7-nitro-4-(3-chloro-4-fluoroanilino)quinazoline.

Refer to the experimental operation of step 2 in Example 1, the only difference is that the reactant aniline in this step is replaced by an equimolar amount of 3-chloro-4-fluoroaniline.

Step 3: Preparation of 7-amino-4-(3-chloro-4-fluoroanilino)quinazoline.

Referring to the experimental operation of step 3 in Example 1, the only difference is that the reactant 7-nitro-4-anilinoquinazoline in this step is replaced with equimolar 7-nitro-4-(3-chloro -4-fluoroanilino)quinazoline.

For step 4, refer to the experimental operation of step 4 in Example 12.

Step 5: Preparation of 1-(2,4-difluorobenzoyl)-3-[4-(3-chloro-4-fluoroanilino)quinazolin-7-yl]urea

Referring to the experimental operation of step 5 in Example 12, the only difference is that the reactant 7-amino-4-anilinoquinazoline in this step is replaced with an equimolar amount of 7-amino-4-(3-chloro- 4-fluoroanilino) quinazoline, the total yield is 26.2%.

Example 26 Synthesis of 1-benzoyl-3-(7-methoxy-4-anilinoquinazolin-6-yl)urea (compound 26)

The synthetic route and method of compound 26 are as follows:

Step 1: Preparation of 7-chloro-3H-quinazolin-4-one

Add 4-chloro-2-aminobenzoic acid (10.26g, 60.0mmol) and formamidine acetate (12.50g, 120.0mmol) into 250mL ethylene glycol monomethyl ether, heat to 120°C, keep the reaction for 16h, and cool to At room temperature, it was concentrated to dryness under reduced pressure, washed with 0.01mol/L ammonia water until neutral, suction filtered, and dried to obtain 9.67 g of off-white solid 7-chloro-3H-quinazolin-4-one with a yield of 89.2%.

Step 2: Preparation of 7-chloro-6-nitro-3H-quinazolin-4-one

Under cooling in an ice-water bath, 7-chloro-3H-quinazolin-4-one (9.00 g, 50.0 mmol) was added in batches to mixed acid (concentrated sulfuric acid 30 mL and fuming nitric acid 30 mL), and after the addition was complete, stir at room temperature for 1 h. Heat to 45°C and stir overnight. Then the reaction solution was poured into 60 mL of ice water, filtered, and the filtered solid was washed with water, recrystallized with acetic acid, and dried to obtain 8.91 g of yellow solid 7-chloro-6-nitro-3H-quinazolin-4-one, which produced The rate is 79.0%.

Step 3: Preparation of 6-nitro-7-methoxy-3H-quinazolin-4-one

7-Chloro-6-nitro-3H-quinazolin-4-one (7.01 g, 31.1 mmol) was dissolved in dry 120 mL of DMF, and then a solution of sodium methoxide (5.45 g, 101.0 mmol) in anhydrous methanol was added ( 120mL), and potassium iodide (5.16g, 31.1mmol), heated to 90°C, and reacted for 20h. The reaction solution was filtered with suction, the filtrate was adjusted to neutral with acetic acid, diluted with water, and a solid was precipitated, filtered with suction to obtain 5.53 g of yellow solid 6-nitro-7-methoxy-3H-quinazolin-4-one, which produced The rate is 80.4%.

Step 4: Preparation of 6-nitro-7-methoxy-4-anilinoquinazoline

6-nitro-7-methoxy-3H-quinazolin-4-one (4.42g, 20.0mmol) was added to 45mL SOCl ₂ solution, then 0.4mL DMF was added, stirred at reflux for 2h, the solution gradually became The brown color was clear, the reaction was stopped, cooled to room temperature, and excess SOCl ₂ was distilled off to obtain 4-chloro-6-nitro-7-methoxyquinazoline as a light yellow solid. The obtained light yellow solid was crushed, 30 mL of petroleum ether was added, the petroleum ether was distilled off under reduced pressure, and the operation of adding petroleum ether was repeated twice to remove residual SOCl ₂ to obtain a yellow solid. Transfer the yellow solid to a three-necked flask without purification, add aniline (2.05 g, 22.0 mmol), and 170 mL of isopropanol, stir at reflux for 2 h, cool to room temperature, collect the solid, wash with isopropanol, and dry to obtain a yellow solid 6 - Nitro-7-methoxy-4-anilinoquinazoline 3.15 g, yield 65.8%.

Step 5: Preparation of 6-amino-7-methoxy-4-anilinoquinazoline

6-Nitro-7-methoxy-4-anilinoquinazoline (2.37g, 8.0mmol) and stannous chloride dihydrate (10.84g, 48.0mmol) were added in 250mL ethyl acetate, reflux reaction 1h. After the reaction is complete, place it at room temperature, filter, and wash the obtained solid with ethyl acetate, combine the ethyl acetate solution, adjust to neutrality with saturated sodium bicarbonate solution, separate the ethyl acetate layer, wash with 30mL water, anhydrous _Na2 Dry over SO ₄ and concentrate to dryness under reduced pressure to obtain 1.92 g of 6-amino-7-methoxy-4-anilinoquinazoline as a tan solid with a yield of 81.1%.

For step 6, refer to the experimental operation of step 4 in Example 1.

Step 7: Preparation of 1-benzoyl-3-(7-methoxy-4-anilinoquinazolin-6-yl)urea

Benzoyl isocyanate (0.32g, 2.2mmol) was added to 20mL of acetonitrile, and 6-amino-7-methoxy-4-anilinoquinazoline (0.53g, 2.0mmol) was added in batches under stirring at room temperature, and Stir for 3h, filter to obtain a solid, wash with acetonitrile, dry, and recrystallize with 80% ethanol to obtain a light yellow solid 1-benzoyl-3-(7-methoxy-4-anilinoquinazoline-6- base) urea (compound 26) 0.64g, the yield was 77.4%.

Example 27 Synthesis of 1-phenyl-3-[7-methoxy-4-(4-chloro-3-trifluoromethylanilino)quinazolin-6-yl]urea (compound 27)

The preparation method is the same as in Example 26, except that the aniline added in step 4 is replaced by 4-chloro-3-trifluoromethylaniline in an equimolar amount, and the reactant 6-nitro-7-methylaniline in step 5 Oxygen-4-anilinoquinazoline is replaced by an equimolar amount of 6-nitro-7-methoxyl-4-(4-chloro-3-trifluoromethylanilino) quinazoline in step 7 The reactant 6-amino-7-methoxyl-4-anilinoquinazoline is replaced by an equimolar amount of 6-amino-7-methoxyl-4-(4-chloro-3-trifluoromethylaniline Base) quinazoline, the total yield is 12.8%.

Example 28 Synthesis of 1-benzoyl-3-[7-methoxy-4-(3-bromoanilino)quinazolin-6-yl]urea (compound 28)

The preparation method is the same as in Example 26, except that the aniline added in step 4 is replaced by an equimolar amount of 3-bromoaniline, and the reactant 6-nitro-7-methoxyl-4-anilino in step 5 Quinazoline is replaced with the 6-nitro-7-methoxyl group-4-(3-bromoanilino) quinazoline of equimolar amount, the reactant 6-amino-7-methoxyl group in step 7 -anilinoquinazoline was replaced by an equimolar amount of 6-amino-7-methoxy-4-(3-bromoanilino)quinazoline, and the total yield was 28.8%.

Example 29 Synthesis of 1-benzoyl-3-[7-methoxy-4-(4-bromoanilino)quinazolin-6-yl]urea (compound 29)

The preparation method is the same as in Example 26, except that the aniline added in step 4 is replaced by an equimolar amount of 4-bromoaniline, and the reactant 6-nitro-7-methoxyl-4-aniline in step 5 is Base quinazoline is replaced with 6-nitro-7-methoxyl group-4-(4-bromoanilino) quinazoline of equimolar amount, reactant 6-amino-7-methoxyl group in step 7 -4-anilinoquinazoline was replaced by an equimolar amount of 6-amino-7-methoxy-4-(4-bromoanilino)quinazoline, and the total yield was 17.8%.

Example 30 Synthesis of 1-benzoyl-3-(4-anilinoquinazolin-6-yl)urea (compound 30)

The synthetic route and method of compound 30 are as follows:

Step 1: Preparation of 6-nitro-3H-quinazolin-4-one

Add 2-amino-5-nitrobenzoic acid (7.28g, 40.0mmol) into 60mL formamide, heat to 120°C, keep warm for 16h, cool to room temperature, precipitate solid, filter, wash with isopropanol, and dry 4.91 g of brown solid 6-nitro-3H-quinazolin-4-one was obtained with a yield of 64.2%.

Step 2: Preparation of 6-nitro-4-(4-fluoroanilino)quinazoline

Add 6-nitro-3H-quinazolin-4-one (2.25g, 11.8mmol) into 23mL of SOCl ₂ solution, then add 0.2mL of DMF, reflux and stir for 1h, the solution gradually becomes brown and clear, stop the reaction, and cool After reaching room temperature, excess SOCl ₂ was distilled off to obtain 4-chloro-6-nitroquinazoline as a yellow solid. The obtained yellow solid was crushed, 10 mL of petroleum ether was added, the petroleum ether was distilled off under reduced pressure, and the operation of adding petroleum ether was repeated twice to remove residual SOCl ₂ to obtain a yellow solid. Add aniline (1.31g, 14.1mmol) and 37mL of isopropanol to the yellow solid without purification, stir at reflux for 2h, a solid precipitates, cool to room temperature, collect the solid by filtration, wash with isopropanol, and dry to give a yellow solid 6- Nitro-4-(4-fluoroanilino)quinazoline 2.19 g, yield 69.7%.

Step 3: Preparation of 6-amino-4-anilinoquinazoline

Mix 6-nitro-4-anilinoquinazoline (1.30g, 4.9mmol), stannous chloride dihydrate (4.42g, 19.6mmol) and ethyl acetate 49mL, and reflux for 1h. The reaction solution becomes clear first, and then precipitates appear. After the reaction is completed, place it at room temperature and filter. The resulting precipitate is washed with ethyl acetate, combined with the ethyl acetate solution, adjusted to neutrality with saturated sodium bicarbonate solution, and the ethyl acetate layer is separated. , washed with 10 mL of water, dried over anhydrous Na ₂ SO ₄ , and concentrated to dryness under reduced pressure to obtain 0.99 g of 6-amino-4-anilinoquinazoline as a yellow solid with a yield of 85.5%.

For step 4, refer to the experimental operation of step 4 in Example 1.

Step 5: Preparation of 1-benzoyl-3-(4-anilinoquinazolin-6-yl)urea

Benzoyl isocyanate (0.32g, 2.2mmol) was added to 20mL acetonitrile, under stirring at room temperature, 6-amino-4-anilinoquinazoline (0.47g, 2.0mmol) was added in batches, stirred at room temperature for 3h, after filtration The obtained solid was washed with acetonitrile, dried, and recrystallized with 80% ethanol to obtain 0.64 g of 1-benzoyl-3-(4-anilinoquinazolin-6-yl)urea (compound 30) as a light yellow solid. The yield was 83.5%.

Example 31 Synthesis of 1-benzoyl-3-[4-(2-methylanilino)quinazolin-6-yl]urea (compound 31)

The preparation method is the same as in Example 30, except that the aniline added in step 2 is replaced by an equimolar amount of 2-methylaniline, and the reactant 6-nitro-4-anilinoquinazoline in step 3 is replaced by Become the 6-nitro-7-methoxyl group-4-(2-methylanilino) quinazoline of equimolar amount, the reactant 6-amino-4-anilino quinazoline in step 5 is replaced by Equimolar amounts of 6-amino-4-(2-methylanilino)quinazoline have a total yield of 17.4%.

Example 32 Synthesis of 1-benzoyl-3-[4-(4-methylanilino)quinazolin-6-yl]urea (compound 32)

The preparation method is the same as in Example 30, except that the aniline added in step 2 is replaced by an equimolar amount of 4-methylaniline, and the reactant 6-nitro-7-methoxy-4- Anilinoquinazoline is replaced with 6-nitro-7-methoxyl group-4-(4-methylanilino) quinazoline of equimolar amount, reactant 6-amino-7-methan in step 5 Oxy-4-anilinoquinazoline was replaced by an equimolar amount of 6-amino-7-methoxy-4-(4-methylanilino)quinazoline, and the total yield was 27.1%.

Example 33 Synthesis of 1-benzoyl-3-[4-(3-bromoanilino)quinazolin-6-yl]urea (compound 33)

The preparation method is the same as in Example 30, except that the aniline added in step 2 is replaced by 3-bromoaniline in an equimolar amount, and the reactant 6-nitro-4-anilinoquinazoline in step 3 is replaced by Equimolar 6-nitro-4-(3-bromoanilino) quinazoline, reactant 6-amino-4-anilinoquinazoline in step 5 is replaced by equimolar 6-amino- 4-(3-Bromoanilino)quinazoline, the total yield is 21.1%.

Example 34 Synthesis of 1-benzoyl-3-[4-(4-fluoroanilino)quinazolin-6-yl]urea (compound 34)

The preparation method is the same as that of Example 30, except that the aniline added in step 2 is replaced by an equimolar amount of 4-fluoroaniline, and the reactant 6-nitro4-anilinoquinazoline in step 3 is replaced by The 6-nitro-4-(4-fluoroanilino) quinazoline of molar quantity, the reactant 6-amino-4-anilino quinazoline in step 5 is replaced with the 6-amino-4 of equimolar quantity -(4-Fluoroanilino)quinazoline, the total yield is 25.6%.

Example 35 Synthesis of 1-benzoyl-3-[4-(3-chloro-4-fluoroanilino)quinazolin-6-yl]urea (compound 35)

The preparation method is the same as in Example 30, except that the aniline added in step 2 is replaced by an equimolar amount of 3-chloro-4-fluoroaniline, and the reactant 6-nitro-4-anilinoquinoline in step 3 is Oxazoline is replaced with 6-nitro-4-(3-chloro-4-fluoroanilino) quinazoline of equimolar amount, and the reactant 6-amino-4-anilino quinazoline in step 5 is replaced with Equimolar amounts of 6-amino-4-(3-chloro-4-fluoroanilino)quinazoline, the total yield is 30.0%.

Example 36 Synthesis of 1-benzoyl-3-[4-(3-cyanoanilino)quinazolin-6-yl]urea (compound 36)

The preparation method is the same as in Example 30, except that the aniline added in step 2 is replaced by 3-cyanoaniline in an equimolar amount, and the reactant 6-nitro4-anilinoquinazoline in step 3 is replaced by The 6-nitro-4-(3-cyanoanilino) quinazoline of equimolar quantity, the reactant 6-amino-4-anilinoquinazoline in step 5 is replaced with the 6-amino of equimolar quantity -4-(3-cyanoanilino)quinazoline, the total yield is 27.8%.

Example 37 Synthesis of 1-benzoyl-3-[7-(4-methylpiperazin-1-yl)-4-anilinoquinazolin-6-yl]urea (compound 37)

The synthetic route and method of compound 37 are as follows:

For Step 1, refer to the experimental operation of Step 1 in Example 26.

For step 2, refer to the experimental operation of step 2 in Example 26.

Step 3: Preparation of 6-nitro-7-chloro-4-(2-methylanilino)quinazoline

Add the 6-nitro-7-chloro-3H-quinazolin-4-one (9.00g, 40.0mmol) obtained above into 90mL SOCl ₂ solution, then add 0.9mL DMF, reflux and stir for 2h, the solution gradually becomes The dark yellow is clear, the reaction is stopped, cooled to room temperature, and excess SOCl ₂ is distilled off to obtain 4,7-dichloro-6-nitroquinazoline as a yellow solid. The yellow solid was crushed, 50 mL of petroleum ether was added, the petroleum ether was distilled off under reduced pressure, and the operation of adding petroleum ether was repeated twice to remove residual SOCl ₂ to obtain a yellow solid. Transfer the yellow solid to a three-necked flask without purification, add 2-methylaniline (4.71g, 44.0mmol), 170mL of isopropanol, stir at reflux for 2h, a solid precipitates, cool to room temperature, collect the solid, and wash with isopropanol , and dried to obtain 9.01 g of yellow solid 6-nitro-7-chloro-4-(2-methylanilino)quinazoline with a yield of 71.6%.

Step 4: Preparation of 6-nitro-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino)quinazoline

6-nitro-7-chloro-4-(2-methylanilino) quinazoline (6.28g, 20.0mmol) was added in N-methylpiperazine (20.0g, 200.0mmol), under nitrogen atmosphere , heated to 70°C, kept warm for 4 hours, cooled to room temperature, evaporated to dryness under reduced pressure, extracted with ethyl acetate, filtered with suction, spin-dried the filtrate, added 60 mL of ethanol to the residue, added 120 mL of distilled water dropwise under stirring, stirred for 30 minutes, and a yellow solid precipitated , and suction filtered to obtain 4.90 g of yellow solid 6-nitro-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino)quinazoline, with a yield of 64.7%.

Step 5: Preparation of 6-amino-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino)quinazoline

6-nitro-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino)quinazoline (3.79g, 10.0mmol), hydrazine hydrate (0.20g, 4.0mmol ) and Raney nickel (7.6mL) were added to ethanol (500mL), heated to reflux under a nitrogen atmosphere, kept for 2 hours, the reaction solution was suction filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was washed with the ester (3:1) mixture, and suction filtered to obtain a yellow solid 6-amino-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino)quinazoline 2.06 g, yield 59.1%.

For step 6, refer to the experimental operation of step 4 in Example 1.

Step 7: Preparation of 1-benzoyl-3-[7-(4-methylpiperazin-1-yl)-4-(2-methylanilino)quinazolin-6-yl]urea

6-Amino-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino)quinazoline (0.70g, 2.0mmol) was dissolved in 20mL acetonitrile at 60°C, and added Benzoyl isocyanate (0.32g, 2.2mmol), reflux for 2h, filter, wash the filter cake with acetonitrile, and dry to obtain light yellow solid 1-benzoyl-3-[7-(4-methylpiperazine-1- Base)-4-(2-methylanilino)quinazolin-6-yl]urea 0.84g, the yield was 84.7%.

Example 38 1-benzoyl-3-[7-(4-methylpiperazin-1-yl)-4-(3-bromoanilino)quinazolin-6-yl]urea (compound 38) synthesis

The preparation method is the same as in Example 37, the difference is that the 2-methylaniline added in step 3 is replaced by an equimolar amount of 3-bromoaniline, and the reactant 6-nitro-7- Chloro-4-(2-methylanilino) quinazoline is replaced by equimolar 6-nitro-7-chloro-4-(3-bromoanilino) quinazoline, the reactant in step 5 6-nitro-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino)quinazoline is replaced by 6-nitro-7-(4-methyl Basepiperazin-1-yl)-4-(3-bromoanilino)quinazoline, reactant 6-amino-7-(4-methylpiperazin-1-yl)-4- (2-methylanilino) quinazoline is replaced by equimolar amounts of 6-amino-7-(4-methylpiperazin-1-yl)-4-(3-bromoanilino) quinazoline, total The yield was 17.6%.

Example 39 1-benzoyl-3-[7-(4-methylpiperazin-1-yl)-4-(2-fluoro-4-bromoanilino)quinazolin-6-yl]urea ( Compound 39) Synthesis

The preparation method is the same as in Example 37, the difference is that the 2-methylaniline added in step 3 is replaced by an equimolar amount of 2-fluoro-4-bromoaniline, and the reactant 6-nitro- 7-chloro-4-(2-methylanilino) quinazoline is replaced by equimolar 6-nitro-7-chloro-4-(2-fluoro-4-bromoanilino) quinazoline, Reactant 6-nitro-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino) quinazoline in step 5 is replaced with 6-nitro- 7-(4-methylpiperazin-1-yl)-4-(2-fluoro-4-bromoanilino)quinazoline, reactant 6-amino-7-(4-methyl Piperazin-1-yl)-4-(2-methylanilino)quinazoline is replaced by 6-amino-7-(4-methylpiperazin-1-yl)-4-(2 -Fluoro-4-bromoanilino)quinazoline, the total yield is 12.4%.

Example 40 1-Benzoyl-3-[7-(4-methylpiperazin-1-yl)-4-(2-methyl-4-methoxyanilino)quinazolin-6-yl ] Synthesis of urea (compound 40)

The preparation method is the same as that of Example 37, except that the 2-methylaniline added in step 3 is replaced by an equimolar amount of 2-methyl-4-methoxyaniline, and the reactant 6-methoxyaniline in step 4 is Nitro-7-chloro-4-(2-methylanilino)quinazoline was replaced by an equimolar amount of 6-nitro-7-chloro-4-(2-methyl-4-methoxyanilino ) quinazoline, the reactant 6-nitro-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino) quinazoline in step 5 is replaced by an equimolar amount The 6-nitro-7-(4-methylpiperazin-1-yl)-4-(2-methyl-4-methoxyanilino) quinazoline, reactant 6- in step 7 Amino-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino)quinazoline was replaced by 6-amino-7-(4-methylpiperazine- 1-yl)-4-(2-methyl-4-methoxyanilino)quinazoline, the total yield is 19.0%.

Example 41 1-benzoyl-3-[7-(4-methylpiperazin-1-yl)-4-(3-bromoanilino)quinazolin-6-yl]urea (compound 41) synthesis

The preparation method is the same as in Example 37, the difference is that the 2-methylaniline added in step 3 is replaced by 4-chloro-3-trifluoromethylaniline in an equimolar amount, and the reactant 6- Nitro-7-chloro-4-(2-methylanilino)quinazoline was replaced by an equimolar amount of 6-nitro-7-chloro-4-(4-chloro-3-trifluoromethylanilino ) quinazoline, the reactant 6-nitro-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino) quinazoline in step 5 is replaced by an equimolar amount The 6-nitro-7-(4-methylpiperazin-1-yl)-4-(4-chloro-3-trifluoromethylanilino) quinazoline, reactant 6- Amino-7-(4-methylpiperazin-1-yl)-4-(2-methylanilino)quinazoline was replaced by 6-amino-7-(4-methylpiperazine- 1-yl)-4-(4-chloro-3-trifluoromethylanilino)quinazoline, the total yield was 15.9%.

Example 42 Synthesis of 1-benzoyl-3-[7-(morpholin-4-yl)-4-anilinoquinazolin-6-yl]urea (compound 42) The synthetic route and method of compound 42 are as follows :

For Step 1, refer to the experimental operation of Step 1 in Example 26.

For step 2, refer to the experimental operation of step 1 in Example 26.

Step 3: Preparation of 6-nitro-7-chloro-4-anilinoquinazoline

Refer to the experimental operation of step 3 in Example 37, the only difference is that the 2-methylaniline added in this step is replaced by aniline in an equimolar amount.

Step 4: Preparation of 6-nitro-7-(morpholin-4-yl)-4-anilinoquinazoline

Add 6-nitro-7-chloro-4-anilinoquinazoline (6.01g, 20.0mmol) into morpholine (17.42g, 200.0mmol), heat to 70°C under a nitrogen atmosphere, and keep the reaction for 4h. Cool to room temperature, evaporate to dryness under reduced pressure, add ethyl acetate to extract, filter with suction, spin dry the filtrate, add 60mL of ethanol to the residue, add 120mL of distilled water dropwise with stirring, stir for 30min, a yellow solid is precipitated, filter with suction to obtain a yellow solid 6-nitrate 4.94 g of 7-(morpholin-4-yl)-4-anilinoquinazoline, yield 70.3%.

Step 5: Preparation of 6-amino-7-(morpholin-4-yl)-4-anilinoquinazoline

Referring to the experimental operation of step 5 in Example 37, the only difference is that the reactant 6-nitro-7-(4-methylpiperazin-1-yl)-4-(2-methylaniline in this step Base) quinazoline is replaced by equimolar amount of 6-nitro-7-(morpholin-4-yl)-4-anilinoquinazoline.

For step 6, refer to the experimental operation of step 4 in Example 1.

Step 7: Preparation of 1-benzoyl-3-[7-(morpholin-4-yl)-4-anilinoquinazolin-6-yl]urea

Referring to the experimental operation of step 7 in Example 37, the only difference is that the reactant 6-amino-7-(4-methylpiperazin-1-yl)-4-(2-methyl Anilino)quinazoline was replaced by an equimolar amount of 6-amino-7-(morpholin-4-yl)-4-anilinoquinazoline, and the total yield was 16.9%.

Example 43 1-benzoyl-3-[7-(morpholin-4-yl)-4-(2-fluoro-4-bromoanilino)quinazolin-6-yl]urea (compound 43) synthesis

The preparation method is the same as in Example 42, the difference is that the aniline added in step 3 is replaced by an equimolar amount of 2-fluoro-4-bromoaniline, and the 6-nitro-7-chloro-4 -anilinoquinazoline is replaced by equimolar amounts of 6-nitro-7-chloro-4-(2-fluoro-4-bromoanilino) quinazoline, the reactant 6-nitro- 7-(morpholin-4-yl)-4-anilinoquinazoline was replaced by an equimolar amount of 6-nitro-7-(morpholin-4-yl)-4-(2-fluoro-4-bromo Anilino) quinazoline, the reactant 6-amino-7-(morpholin-4-yl)-4-anilinoquinazoline in step 7 is replaced by 6-amino-7-(morpholine Lin-4-yl)-4-(2-fluoro-4-bromoanilino)quinazoline, the total yield was 14.4%.

Example 44 1-benzoyl-3-[7-(morpholin-4-yl)-4-(3-chloro-4-fluoroanilino)quinazolin-6-yl]urea (compound 44) synthesis

The preparation method is the same as in Example 42, the difference is that the aniline added in step 3 is replaced by an equimolar amount of 3-chloro-4-fluoroaniline, and the 6-nitro-7-chloro-4 -anilinoquinazoline is replaced by equimolar amounts of 6-nitro-7-chloro-4-(3-chloro-4-fluoroanilino) quinazoline, the reactant 6-nitro- in step 5 7-(morpholin-4-yl)-4-anilinoquinazoline was replaced by an equimolar amount of 6-nitro-7-(morpholin-4-yl)-4-(3-chloro-4-fluoro Anilino) quinazoline, the reactant 6-amino-7-(morpholin-4-yl)-4-anilinoquinazoline in step 7 is replaced by 6-amino-7-(morpholine Lin-4-yl)-4-(3-chloro-4-fluoroanilino)quinazoline, the total yield was 17.6%.

Example 45 Synthesis of 1-benzoyl-3-(6-methoxy-4-anilinoquinazolin-7-yl)urea (compound 45)

The synthetic route and method of compound 45 are as follows:

Step 1: Synthesis of N-(2-methyl-4-methoxy-phenyl)acetamide

4-Methoxy-2-methylaniline (18.40g, 134.1mmol) was added dropwise to a mixed solution of acetic anhydride (13.69g, 134.1mmol) and 140mL of acetic acid, heated to 60°C, kept for 30min, and then Concentrate to dryness under reduced pressure, dissolve the residue with 80 mL of ethyl acetate, adjust the pH to 8.0 with saturated sodium bicarbonate solution, separate the ethyl acetate layer, wash with distilled water and saturated brine, dry _over anhydrous _Na2SO4 , and concentrate under reduced pressure to After drying, 18.81 g of yellow solid N-(2-methyl-4-methoxy-phenyl)acetamide was obtained with a yield of 78.3%.

Step 2: N-(2-Methyl-4-methoxy-5-nitrophenyl)acetamide

N-(2-methyl-4-methoxy-phenyl)acetamide (16.18g, 90.3mmol) was dissolved in 166ml of trifluoroacetic acid, and cooled to 0°C in an ice-water bath. Potassium nitrate (10.11 g, 100.0 mmol) was slowly added and stirred at room temperature for 1 h. Pour the reaction solution into ice water to quench, extract with ethyl acetate (2×50 mL), combine the ethyl acetate solutions, adjust to neutral with saturated sodium bicarbonate solution, wash with distilled water and saturated brine, anhydrous Na ₂ SO ₄ was dried, concentrated to dryness under reduced pressure, the residue was added to 100 mL of ethyl acetate, stirred for 1 h, and filtered with suction to obtain a yellow solid N-(2-methyl-4-methoxy-5-nitrophenyl)acetamide 16.42 g, the yield is 81.1%.

Step 3: 2-Acetamido-5-methoxy-4-nitrobenzoic acid

N-(2-Methyl-4-methoxy-5-nitrophenyl)acetamide (15.04g, 67.1mmol) was added to magnesium sulfate (10.11g, 84.0mmol) and potassium permanganate (29.22g , 184.9mmol) in 671mL aqueous solution, heated to 80°C, reacted for 45min, added magnesium sulfate (5.08g, 42.2mmol) and potassium permanganate (14.63g, 92.6mmol), reacted for 1h. Suction filtration, the filter cake was washed with hot water (2×300mL). The filtrate was acidified with 3.0N HCl solution to pH 3.0, 300 mL of dichloromethane was added to separate the liquid, extracted with dichloromethane (2×200 mL), the dichloromethane solution was combined, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain Yellow solid 2-acetamido-5-methoxy-4-nitrobenzoic acid 11.79g, yield 69.1%.

Step 4: 2-Amino-5-methoxy-4-nitrobenzoic acid

2-Acetamido-5-methoxy-4-nitrobenzoic acid (10.67g, 42.0mmol) was added to a mixture of 38mL distilled water and 15mL concentrated hydrochloric acid, refluxed for 3h, cooled to 0°C, and a solid was precipitated. Suction filtration, washing with distilled water, and drying gave 7.62 g of yellow solid 2-amino-5-methoxy-4-nitrobenzoic acid with a yield of 85.5%.

Step 5: 6-Methoxy-7-nitro-3H-quinazolin-4-one

Add 2-amino-5-methoxy-4-nitrobenzoic acid (6.70g, 31.5mmol) into 100mL formamide, heat to 150°C, keep the reaction for 4.5h, cool to 0°C, a solid precipitates, pump Filter and dry under reduced pressure to obtain 4.93 g of yellow solid 6-methoxy-7-nitro-3H-quinazolin-4-one with a yield of 70.8%.

Step 6: 6-Methoxy-7-nitro-4-anilinoquinazoline

The above-obtained 6-methoxy-7-nitro-3H-quinazolin-4-one (4.42g, 20.0mmol) was added to 44mL of SOCl ₂ solution, and then 0.4mL of DMF was added, stirred at reflux for 2h, and the solution gradually It becomes dark yellow and clear, the reaction is stopped, cooled to room temperature, and excess SOCl ₂ is distilled off to obtain 4-chloro-6-methoxy-7-nitroquinazoline as a yellow solid. The yellow solid was crushed, 10 mL of petroleum ether was added, the petroleum ether was distilled off under reduced pressure, and the operation of adding petroleum ether was repeated twice to remove residual SOCl ₂ to obtain a yellow solid. Transfer the yellow solid to a three-necked flask without purification, add aniline (2.04g, 22.0mmol) and 70mL of isopropanol, stir at reflux for 2h, a solid precipitates, cool to room temperature, collect the solid, wash with isopropanol, and dry to obtain Yellow solid 6-methoxy-7-nitro-4-anilinoquinazoline 4.70 g, yield 79.3%.

Step 7: 6-Methoxy-7-amino-4-anilinoquinazoline

6-methoxy-7-nitro-4-anilinoquinazoline (5.92g, 20.0mmol) and stannous chloride dihydrate (18.05g, 80.0mmol) were added in 250mL ethyl acetate, and the reaction was carried out under reflux 1h. After the reaction is complete, place it at room temperature, filter, and wash the obtained solid with ethyl acetate, combine the ethyl acetate solution, adjust to neutrality with saturated sodium bicarbonate solution, separate the ethyl acetate layer, wash with 30mL water, anhydrous _Na2 Dry over SO ₄ and concentrate to dryness under reduced pressure to obtain 4.48 g of 6-methoxy-7-amino-4-anilinoquinazoline as a light yellow solid with a yield of 84.1%.

For step 8, refer to the experimental operation of step 4 in Example 1.

Step 9: 1-Benzoyl-3-(6-methoxy-4-anilinoquinazolin-7-yl)urea

Benzoyl isocyanate (0.32g, 2.2mmol) was added to 10mL of acetonitrile solution, and 6-methoxy-7-amino-4-anilinoquinazoline (0.53g, 2.0mmol) was added in batches under stirring at room temperature, Stir at room temperature for 3 h, filter to obtain a solid, wash with acetonitrile (5 mL×3), dry, add the obtained solid to 30 ml of methanol, reflux for 1 h, and suction filter while hot to obtain a light yellow solid 1-benzoyl-3-(6- Methoxy-4-anilinoquinazolin-7-yl)urea 0.67 g, yield 81.0%.

Example 46 Synthesis of 1-benzoyl-3-[6-(4-methylpiperazin-1-yl)-4-anilinoquinazolin-7-yl]urea (compound 46)

The synthetic route and method of compound 46 are as follows:

Step 1: Synthesis of N-(2-methyl-4-chloro-phenyl)acetamide

Add 4-chloro-2-methylaniline (18.98g, 134.1mmol) dropwise to a mixed solution of acetic anhydride (13.69g, 134.1mmol) and 140mL of acetic acid, heat to 60°C, keep the reaction for 60min, and concentrate under reduced pressure To dryness, the residue was dissolved in 80 mL of ethyl acetate, and the pH was adjusted to 8.0 with saturated sodium bicarbonate solution. The ethyl acetate layer was separated, washed with distilled water and saturated brine, dried over anhydrous Na ₂ SO ₄ , and concentrated to dryness under reduced pressure. 16.18 g of yellow solid N-(2-methyl-4-chloro-phenyl)acetamide was obtained with a yield of 65.7%.

Step 2: N-(2-Methyl-4-chloro-5-nitrophenyl)acetamide

N-(2-methyl-4-chloro-phenyl)acetamide (16.58g, 90.3mmol) was dissolved in 166ml of trifluoroacetic acid and cooled to 0°C in an ice-water bath. Potassium nitrate (10.11 g, 100.0 mmol) was slowly added and stirred at room temperature for 1 h. Pour the reaction solution into ice water to quench, extract with ethyl acetate (2×50 mL), combine the ethyl acetate solutions, adjust to neutral with saturated sodium bicarbonate solution, wash with distilled water and saturated brine, anhydrous Na ₂ SO ₄ was dried, concentrated to dryness under reduced pressure, the residue was added to 100 mL of ethyl acetate, stirred for 1 h, and filtered with suction to obtain 17.69 g of yellow solid N-(2-methyl-4-chloro-5-nitrophenyl)acetamide, The yield was 85.7%.

Step 3: 2-Acetamido-5-chloro-4-nitrobenzoic acid

N-(2-Methyl-4-chloro-5-nitrophenyl)acetamide (15.34g, 67.1mmol) was added to magnesium sulfate (10.11g, 84.0mmol) and potassium permanganate (29.22g, 184.9 mmol) in 671mL aqueous solution, the temperature was raised to 80°C, and after reacting for 45min, magnesium sulfate (5.08g, 42.2mmol) and potassium permanganate (14.63g, 92.6mmol) were added and reacted for 1h. Suction filtration, the filter cake was washed with hot water (2×300mL). The filtrate was acidified with 3.0N HCl solution to pH 3.0, 300 mL of dichloromethane was added to separate the liquid, extracted with dichloromethane (2×200 mL), the dichloromethane solution was combined, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to obtain Yellow solid 2-acetamido-5-chloro-4-nitrobenzoic acid 11.00 g, yield 63.4%.

Step 4: 2-Amino-5-chloro-4-nitrobenzoic acid

Add 2-acetamido-5-chloro-4-nitrobenzoic acid (10.86g, 42.0mmol) into a mixture of 38mL distilled water and 15mL concentrated hydrochloric acid, reflux for 3h, cool to 0°C, precipitate a solid, and filter with suction , washed with distilled water, and dried to obtain 7.92 g of yellow solid 2-amino-5-chloro-4-nitrobenzoic acid with a yield of 87.1%.

Step 5: 6-Chloro-7-nitro-3H-quinazolin-4-one

Add 2-amino-5-chloro-4-nitrobenzoic acid (6.82g, 31.5mmol) into 100mL formamide, heat to 150°C, keep the reaction for 4.5h, cool to 0°C, precipitate solid, suction filter, Drying under reduced pressure gave 6.30 g of yellow solid 6-chloro-7-nitro-3H-quinazolin-4-one with a yield of 88.7%.

Step 6: 6-Chloro-7-nitro-4-anilinoquinazoline

Add the 6-chloro-7-nitro-3H-quinazolin-4-one (4.51g, 20.0mmol) obtained above into 45mL SOCl ₂ solution, then add 0.4mL DMF, reflux and stir for 2h, the solution gradually becomes The dark yellow is clear, the reaction is stopped, cooled to room temperature, and excess SOCl ₂ is distilled off to obtain 4,6-dichloro-7-nitroquinazoline as a yellow solid. The yellow solid was crushed, 10 mL of petroleum ether was added, the petroleum ether was distilled off under reduced pressure, and the operation of adding petroleum ether was repeated twice to remove residual SOCl ₂ to obtain a yellow solid. Transfer the yellow solid to a three-necked flask without purification, add aniline (2.04g, 22.0mmol) and 70mL of isopropanol, stir at reflux for 2h, a solid precipitates, cool to room temperature, collect the solid, wash with isopropanol, and dry to obtain Yellow solid 6-chloro-7-nitro-4-anilinoquinazoline 3.87g, yield 64.3%.

Step 7: Preparation of 6-(4-methylpiperazin-1-yl)-7-nitro-4-anilinoquinazoline

Add 6-chloro-7-nitro-4-anilinoquinazoline (6.01g, 20.0mmol) into N-methylpiperazine (20.0g, 200.0mmol), and heat to 70°C under nitrogen atmosphere, Heat preservation reaction for 4 hours, cool to room temperature, evaporate to dryness under reduced pressure, add ethyl acetate to extract, filter with suction, spin dry the filtrate, add 60mL of ethanol to the residue, add 120mL of distilled water dropwise under stirring, stir for 30min, a yellow solid precipitates, and filter with suction to obtain yellow Solid 6-(4-methylpiperazin-1-yl)-7-nitro-4-anilinoquinazoline 6.45 g, yield 88.5%.

Step 8: Preparation of 6-(4-methylpiperazin-1-yl)-7-amino-4-methylanilinoquinazoline

6-(4-methylpiperazin-1-yl)-7-nitro-4-anilinoquinazoline (3.64g, 10.0mmol), hydrazine hydrate (0.20g, 4.0mmol) and Raney nickel ( 7.6mL) was added to ethanol (500mL), heated to reflux under a nitrogen atmosphere, kept for 2 hours, the reaction solution was suction-filtered, and the filtrate was evaporated to dryness under reduced pressure, using petroleum ether and ethyl acetate (3:1) The residue was washed with the mixed liquid, and suction-filtered to obtain 2.71 g of 6-(4-methylpiperazin-1-yl)-7-amino-4-anilinoquinazoline as a yellow solid, with a yield of 81.0%.

For step 9, refer to the experimental operation of step 4 in Example 1.

Step 10: 1-Benzoyl-3-[6-(4-methylpiperazin-1-yl)-4-anilinoquinazolin-7-yl]urea

6-(4-methylpiperazin-1-yl)-7-amino-4-anilinoquinazoline (0.67g, 2.0mmol) was dissolved in 20mL acetonitrile at 60°C, and benzoyl isocyanate (0.32 g, 2.2mmol), reflux for 2h, filter, wash the filter cake with acetonitrile, and dry to obtain off-white solid 1-benzoyl-3-[6-(4-methylpiperazin-1-yl)-4-aniline Quinazolin-7-yl]urea 0.69g, the yield was 71.6%.

Example 47 Synthetic intermediate of 1-benzoyl-3-[6-(morpholin-4-yl)-4-anilinoquinazolin-7-yl]urea (compound 47) 6-chloro-7- The preparation method of nitro-4-anilinoquinazoline is the same as steps 1-6 in Example 46.

Step 7: Preparation of 6-(morpholin-4-yl)-7-nitro-4-anilinoquinazoline

Add 6-chloro-7-nitro-4-anilinoquinazoline (6.01g, 20.0mmol) into morpholine (17.42g, 200.0mmol), heat to 70°C under a nitrogen atmosphere, and keep the reaction for 4h. Cool to room temperature, evaporate to dryness under reduced pressure, add ethyl acetate to extract, suction filter, spin dry the filtrate, add 60 mL of ethanol to the residue, add 120 mL of distilled water dropwise under stirring, stir for 30 min, a yellow solid is precipitated, and suction filtered to obtain a yellow solid 6-( Morpholin-4-yl)-7-nitro-4-anilinoquinazoline 5.30 g, yield 75.4%.

Step 8: Preparation of 6-(morpholin-4-yl)-7-amino-4-anilinoquinazoline

Referring to the experimental operation of step 8 in Example 46, the only difference is that the reactant 6-(4-methylpiperazin-1-yl)-7-nitro-4-anilinoquinazoline in this step is replaced into equimolar amounts of 6-(morpholin-4-yl)-7-nitro-4-anilinoquinazoline.

For step 9, refer to the experimental operation of step 4 in Example 1.

Step 10: Preparation of 1-benzoyl-3-[6-(morpholin-4-yl)-4-anilinoquinazolin-7-yl]urea

Referring to the experimental operation of step 10 in Example 46, the only difference is that the reactant 6-(4-methylpiperazin-1-yl)-7-amino-4-anilinoquinazoline in this step is replaced by Equimolar amounts of 6-(morpholin-4-yl)-7-amino-4-anilinoquinazoline.

Example 48 Synthesis of 1-benzoyl-3-(7-methoxy-4-anilinoquinazolin-6-yl)urea hydrochloride (compound 48)

The synthetic route and method of compound 48 are as follows:

Prepare 1-benzoyl-3-(7-methoxy-4-anilinoquinazolin-6-yl) urea in the same manner as in Example 26, prepare 1-benzoyl-3-( 7-methoxy-4-anilinoquinazolin-6 ^- yl)urea (0.2g, 0.48× ^10-3 mol) was dissolved in a mixed solution of ethanol and dichloroethane (3:7), and 2N Hydrochloric acid ethanol solution (2mL) was filtered, and the filter cake was dried to obtain white solid 1-benzoyl-3-(7-methoxy-4-anilinoquinazolin-6-yl)urea hydrochloride, yield 84.6 %.

Table 1 lists the molecular structures and characterizations of compounds 1-48 obtained according to Examples 1-48 of the present invention.

Test Example 1 Determination of 1-benzoyl-3-[4-(4-methylanilino)quinazolin-7-yl]urea (compound 2)

Chromatographic conditions: C ₁₈ chromatographic column (Luna 250×4.6mm 5μ), mobile phase, acetonitrile:water=25:75, flow rate: 1.0mL/min, detection wavelength: 254nm, injection volume: 10μL.

System suitability test: Take the compound 2 control solution (3mg/mL) and inject it under chromatographic conditions. The theoretical plate number is 5420 based on the compound 2 peak, and the retention time is 18.24min.

Limit of detection and limit of quantification: Taking S/N of 3 and 10 as the investigation indicators respectively, the detection limit of compound 2 was measured to be 100ng, and the limit of quantification was 300ng.

Reproducibility experiment: under chromatographic conditions, the reference substance solution was continuously injected 5 times, the relative standard deviation (RSD) of the peak elution time of compound 2 was 0.25%, and the RSD of the peak area was 0.20%.

Sample determination: small test product solution (3mg/mL) was injected and determined under chromatographic conditions. Using the above separation method, according to the area normalization method, three batches of compound 2 small test samples were respectively checked for content. The experimental results (as shown in Table 3) showed that the contents of the three batches of samples were not less than 99%.

Table 3: Batch sample (compound 2) purity check results

The preparation of preparation preparation embodiment 1 pharmaceutical composition (tablet)

Take 10g of compound 2, add 220g of compressible starch, 60g of sucrose, and 6g of magnesium stearate, mix well, and directly compress the powder into 500 tablets, and coat with film.

Test Example 2 Antitumor Activity Screening of Some Compounds

1) Test material

Tested drugs: 47 kinds of aroylurea-coupled quinazoline compounds (compound 1-47) synthesized in the present invention, positive control drugs Gefitinib, Vandetanib, cisplatin (Cisplatin), all drug purity > 99.5%.

Reagents and instruments: DMEM medium (Gibco BRL); calf serum (HyClone) trypsin (Amresco); thiazolyl blue (MTT, Sigma); TK activity analysis enzyme-linked immunosorbent assay (enzyme-linked immunosorbentassay, ELISA) test kit (Chenicon); the rest of the reagents were domestic analytical reagents. The cell culture system was produced by Costar Company; the constant temperature CO ₂ incubator was purchased from Heraeus Company; the microplate reader was produced by Austria TECAN-SUNRISE, model F039246A.

Cell lines: human non-small cell lung adenocarcinoma cell line A549; human lung cancer cell line NCI-H2921 (lymph node metastasis).

2) Tumor cell line culture

A549 and NCI-H2921 cell lines were grown in DMEM medium containing 10% calf serum and double antibodies (penicillin 100U·mL ^-1 , streptomycin 100μg·mL ^-1 ), in a 5% constant temperature incubator at 37°C After culturing, the cells in the logarithmic growth phase were taken for experiments.

3) Determination of cell viability

The cells in the logarithmic growth phase were digested into a single-cell suspension with 0.25% trypsin and evenly inoculated in a 96-well culture plate for routine culture. After the cells grew to a single layer, the original medium was discarded, randomly grouped, and the cells containing each Serum-free DMEM of the test and positive drug was treated at 37°C for 48 hours, then the medium was replaced, 20 μl of MTT (5 mg·mL ^-1 ) was added to each well, and after 4 hours of reaction at 37°C, the liquid in the well was sucked out, and 150 μl of DMSO analytically pure The solution was shaken for 10 min, and the absorbance OD value was measured at a wavelength of 490 nm with a microplate reader. Cell viability (%)=OD value of the administration group/OD of the control group×100%.

4) TK activity analysis

A549 cells in the logarithmic growth phase were washed with ice-cold D-Hank’s solution, then added to the lysate and lysed on ice for 10 minutes, and the cells were collected, centrifuged at 4°C and a relative centrifugal force of 12,000g for 10 minutes, and the crude extract of TK cells was extracted. The effective compounds for the primary screening of A549 cell line MTT were selected to react with the crude extract of TK cells at 37°C for 20min, and the analysis solution and substrate peptide were added to incubate at 30°C for 45min, and then the reaction was terminated with EDTA. Take 50 μl of the reaction system of each group to the enzyme-labeled wells at 37°C for 30 minutes, wash and block for 30 minutes, incubate with PY20-HRP antibody at room temperature for 1 hour, and shake on a shaker. After washing, react with tetramethylbenzidine (TMB) for 15 min, and measure the absorbance at a wavelength of 450 nm with a microplate reader.

5) Cell proliferation test method (MTT method)

In the D-MEM/hams medium containing 20% fetal bovine serum, adjust the tested cells to a suspension with a density of 2×10 ⁵ cells/mL. Inoculate the suspension of the above tumor cell lines in a 96-well culture plate, 50 μl per well, add 50 μl each of blank control phosphate buffer saline (PBS), solvent control 0.1% dimethyl sulfoxide, and monomeric compounds of different concentrations, each group 3 replicate holes were set. Place the above-mentioned 96-well culture plate in a saturated humidity, 37°C and 5% _CO2 incubator for 48 hours, and 4 hours before the end of the culture, add 10 μl of 5 mg/mL tetrazolium salt (MTT) to each culture well, and the culture ends. Finally, discard the culture supernatant, centrifuge the suspended cells and discard the supernatant, add 150 μl of reaction stop solution to each well, let it stand for 1 hour, detect the absorbance (OD) value of each well with an enzyme-linked immunosorbent assay instrument, and measure the wavelength λ=570nm, reference wavelength λ=630nm, and calculate the survival rate of tumor cells.

The compound of the present invention was dissolved in DMSO, and the final concentration after addition was 0.1% or less. The medium supplemented with DMSO was used as a control.

The results of the tumor cell proliferation inhibitory activity of the compounds of the present invention (relative to the control (DMSO added)) are shown in Table 4.

6) Data statistics and analysis

The experimental data were expressed as mean±SEM (mean±standard deviation), and the differences among the values of each group were tested by One-way ANOVA combined with Tukey. P<0.05 means statistical significance.

7) Results

The effect of the new compound on the cell proliferation of each tumor cell line: the new compound with a concentration of 10 μM (3 replicate wells/group) was reacted with each cell line for 48 hours, and the effect of the new compound on the proliferation of tumor cells was observed by MTT method (X- is tumor survival Rate). The results are shown in Table 4:

Table 4: Cell activity screening data of compound 1-47 by MTT method

NCI-H2921

8) Conclusions: as seen from Table 4, compared with the reference drugs Gefitinib (Gefitinib), Vandetanib (Vandetanib), and Cisplatin (Cisplatin), the compound of the present invention has a greater effect on A549 after screening for antitumor activity. For cells (EGFR-TKIs insensitive strains), compounds 2, 9, 20, 27, 33 and 44 showed strong anti-tumor activity, and the tumor cell survival rate was lower than that of the control drug, and the other The compounds also showed strong antitumor activity.

For NCI-H2921 cells, compounds 2, 4, 9, 10 and 33 showed strong anti-tumor activity, and their tumor cell survival rate was lower than that of the control drug, and other compounds also showed Strong antitumor activity. This shows that the compounds of the present invention can effectively treat tumor-related diseases, especially malignant tumors.

Test Example 3 Determination of the Activity of Inhibiting Tubulin Polymerization in Vitro

1. Experimental method

A Experimental materials: The tubulin kit required for this experiment was purchased from Cytoskeleton Company, and the tubulin in the kit was tubulin extracted from bovine brain.

B Add the buffer containing 20% glycerol, 1 mMGTP, 80 mM PIPES with a p of 6.9, 2.0 mM MgCl ₂ , and 0.5 mM EGTA to the tubulin kit, then place it on ice and incubate for 4 hours.

C. Under the condition of 37°C, in the above tubulin polymerization-depolymerization reaction system, the experimental group added solutions of different concentrations of test compounds (2, 9, 33) so that the final concentrations were 3, 0.75, 0.1875 μM; Combretastatin-4 was added to the positive control group to make the final concentrations respectively 3, 0.75, and 0.1875 μM; sterile triple-distilled water was added to the blank control group to replace the above-mentioned test compounds.

The effect of each group on tubulin polymerization can be dynamically detected by a fluorescent microplate reader. According to the inhibition rate obtained from the test, calculate its half inhibitory concentration.

2. The results of the determination of the activity of inhibiting tubulin polymerization in vitro.

It can be seen from the above table that compounds 2, 9, and 33 showed high-efficiency tubulin polymerization inhibition activity close to that of Combretastatin-4 (IC ₅₀ values were in the same order of magnitude). The results showed that the two types of compounds were potent mitogenic compounds, and their targets were tubulin.

Test Example 4 Anti-tumor activity experiment of some compounds in tumor-planted animal models

1. Inoculation of fat tumor cells

Human SW620 colon cancer cells were routinely cultured in a culture solution containing 10% fetal bovine serum at 37°C in a 5% CO ₂ incubator until the required amount of SW620 cells was reached, and the cells were digested and collected. Inject ^1x107 SW620 cells into the armpit of nude mice. After the spleen tumor grows to ^1000mm3 , take the tumor and cut it into ^1mm3 size, and inoculate it subcutaneously. After the spleen tumor grows to ^300mm3 , the nude mice are randomly divided into groups And administer medicines as required.

2. Grouping and dosing regimen

From 50 nude mice pre-inoculated with SW620, 18 nude mice with uniform lung tumor volume were randomly divided into 3 groups: 1) negative control group, 6 mice, and intraperitoneal injection of solvent control saline 0.1ml/10g; 2) compound 26 rats were given 6.25mg/kg by intraperitoneal injection three times a week; 3) 6 rats in the control drug group were given cisplatin 30mg/kg by tail vein injection three times a week; the administration cycle was 20 days, and the interval between administration The tumor volume was weighed and measured, and the nude mice were weighed and sacrificed on the 21st day, and the tumor mass was weighed to calculate the relative tumor proliferation rate (T/C) and tumor inhibition percentage. The corresponding calculation formula is as follows:

Tumor volume calculation formula: v=1/2(a×b ² ), where a is the diameter of the tumor, that is, the length, and b is the transverse diameter of the tumor, that is, the width.

Relative tumor volume RTV calculation formula: RTV=V _t /V ₀ . Among them, Vt is the measured tumor volume at a certain time, and V ₀ is the tumor volume at the first day of administration.

The formula for calculating the relative tumor proliferation rate: T/C (%)=TRTV/CRTV×100%. Among them, TRTV is the relative tumor volume of the treatment group, and CRTV is the relative tumor volume of the lysed control group.

The formula for calculating the percentage of tumor inhibition: tumor inhibition rate=(tumor weight of dissection control group−tumor weight of administration group)/tumor weight of solvent control group×100%.

3. Result Analysis

Using the human colon cancer SW620 nude mouse xenograft model, we evaluated the in vivo inhibitory effect of the compound on tumor growth in two months. The dosing regimen was intraperitoneal injection of 6.25 mg/kg of compound 2, and the tumor volume in the axilla of nude mice was recorded on time. After 20 days of observing the tumor growth in the axilla of mice, we found that at the end of the experiment, the tumor volume of the negative control group (988.6±389.8mm ³ ) and the control drug cisplatin 30mg/kg tumor volume (523.3±321.8mm ³ ) In contrast, the fat tumor volume of the compound 2 group (6.25mg/kg) was (236.4±258.8mm ³ ); compared with the average RTV value (13.3) of the negative control group and the average RTV value (9.2) of the reference drug cisplatin 30mg/kg Ratio, the average of compound 2 group 6.25mg/kg is 3.3, has significant difference (p＜0.001) with negative control group and control drug group; In addition, the T/C (%) of compound 2 group (6.25mg/kg) The value is 35.1. From the above results, it can be concluded that compound 2 group (6.25 mg/kg) can more significantly inhibit the growth of colon cancer SW620 tumors compared with the control drug group, and in the whole experimental process, no occurrence Apparent drug non-response.

The above description of the specific embodiments of the present invention does not limit the present invention, and those skilled in the art can make various changes or deformations according to the present invention, as long as they do not depart from the spirit of the present invention, all should belong to the scope of the appended claims of the present invention.

Claims (15)

1. fragrant formyl urea coupling quinazoline compounds or its pharmaceutically acceptable salt shown in a kind of formula (I),

Wherein, R₁For H；Br, Cl or F；-CH₃、-CH₂-CH₃、-CH₂(CH₃)₂Or-CF₃；-O-CH₃、-O-CH₂-CH₃Or-O-CH₂ (CH₃)₂；- C ≡ CH or-C ≡ N；

n₁It is 1,2,3,4 or 5；

R₂Or R₃One of for group shown in formula (II)；

Wherein, R₄For H；Br, Cl or F；-CH₃、-CH₂-CH₃、-CH₂(CH₃)₂Or-CF₃；-O-CH₃、-O-CH₂-CH₃Or-O-CH₂ (CH₃)₂；-NH₂；Or-NO₂；

n₂It is 1,2,3,4 or 5；

R₂Or R₃In another be H ,-O-CH₃、-O-CH₂-CH₃、-O-CH₂(CH₃)₂、

2. virtue formyl urea coupling quinazoline compounds according to claim 1 or its pharmaceutically acceptable salt, special Sign is that fragrant formyl urea coupling quinazoline compounds shown in the formula (I) are selected from following compound：

1- benzoyls -3- (4- anilinoquinazoline -7- bases) urea

1- benzoyls -3- [4- (2-aminotoluene base) quinazoline -7- bases] urea

1- benzoyls -3- [4- (3- toluidines) quinazoline -7- bases] urea

1- benzoyls -3- [4- (4- toluidines) quinazoline -7- bases] urea

1- benzoyls -3- [4- (2- chloroanilinos) quinazoline -7- bases] urea

1- benzoyls -3- [4- (4- fluoroanilinos) quinazoline -7- bases] urea

1- benzoyls -3- [4- (3- cumenes amido) quinazoline -7- bases] urea

1- benzoyls -3- [4- (4- methoxybenzenes amido) quinazoline -7- bases] urea

1- benzoyls -3- [4- (the bromo- 3- fluoroanilinos of 4-) quinazoline -7- bases] urea

1- benzoyls -3- [4- (2,4- difluorobenzene amido) quinazoline -7- bases] urea

1- benzoyls -3- [4- (2,4,6- trimethylbenzene amido) quinazoline -7- bases] urea

1- benzoyls -3- [4- (2,3- accelerine base) quinazoline -7- bases] urea

1- benzoyls -3- [4- (3- trifluoromethylbenzenes amido) quinazoline -7- bases] urea

1- (2- methyl benzoyls) -3- [4- (2- chloroanilinos) quinazoline -7- bases] urea

1- (4- methyl benzoyls) -3- [4- (3- toluidines) quinazoline -7- bases] urea

1- (4- methyl benzoyls) -3- [4- (3- cumenes amido) quinazoline -7- bases] urea

1- (4- chlorobenzene formacyls) -3- [4- (3- cumenes amido) quinazoline -7- bases] urea

1- (2,6- difluoro benzoyl) -3- [4- anilinoquinazoline -7- bases] urea

1- (2,6- difluoro benzoyl) -3- [4- (2-aminotoluene base) quinazoline -7- bases] urea

1- (2,6- difluoro benzoyl) -3- [4- (2- chloroanilinos) quinazoline -7- bases] urea

1- (2,6- difluoro benzoyl) -3- [4- (2,3- accelerine base) quinazoline -7- bases] urea

1- (2,6- difluoro benzoyl) -3- [4- (2,4- difluorobenzene amido) quinazoline -7- bases] urea

1- (2,6- difluoro benzoyl) -3- [4- (the chloro- 4- fluoroanilinos of 3-) quinazoline -7- bases] urea

1- (2,6- difluoro benzoyl) -3- [4- (the bromo- 3- fluoroanilinos of 4-) quinazoline -7- bases] urea

1- (2,6- difluoro benzoyl) -3- [4- (3- trifluoromethylbenzenes amido) quinazoline -7- bases] urea

1- benzoyls -3- (4- anilinoquinazoline -6- bases) urea

1- benzoyls -3- [4- (4- fluoroanilinos) quinazoline -6- bases] urea

1- benzoyls -3- [4- (2-aminotoluene base) quinazoline -6- bases] urea

1- benzoyls -3- [4- (4- toluidines) quinazoline -6- bases] urea

1- benzoyls -3- [4- (3- cyano-anilines base) quinazoline -6- bases] urea

1- benzoyls -3- [4- (3- bromobenzenes amido) quinazoline -6- bases] urea

1- benzoyls -3- [4- (the chloro- 4- fluoroanilinos of 3-) quinazoline -6- bases] urea

1- benzoyls -3- (7- methoxyl group -4- anilinoquinazoline -6- bases)-urea

1- benzoyls -3- [7- methoxyl groups -4- (the chloro- 3- trifluoromethylbenzenes amidos of 4-) quinazoline -6- bases]-urea

1- benzoyls -3- [7- methoxyl groups -4- (4- bromobenzenes amido) quinazoline -6- bases]-urea

1- benzoyls -3- [7- methoxyl groups -4- (3- bromobenzenes amido) quinazoline -6- bases]-urea

1- benzoyls -3- [7- (4- methylpiperazine-1-yls) -4- (2-aminotoluene base) quinazoline -6- bases] urea

1- benzoyls -3- [7- (4- methylpiperazine-1-yls) -4- (3- bromobenzenes amido) quinazoline -6- bases] urea

1- benzoyls -3- [7- (morpholine -4- bases) -4- anilinoquinazoline -6- bases] urea

1- benzoyls -3- [7- (morpholine -4- bases) -4- (the fluoro- 4- bromobenzenes amidos of 2-) quinazoline -6- bases] urea

1- benzoyls -3- [7- (morpholine -4- bases) -4- (the chloro- 4- fluoroanilinos of 3-) quinazoline -6- bases] urea

1- benzoyls -3- (6- methoxyl group -4- anilinoquinazoline -7- bases) urea

1- benzoyls -3- [6- (4- methylpiperazine-1-yls) -4- anilinoquinazoline -7- bases] urea

1- benzoyls -3- [7- (4- methylpiperazine-1-yls) -4- (the fluoro- 4- bromobenzenes amidos of 2-) quinazoline -6- bases] urea

1- benzoyls -3- [7- (4- methylpiperazine-1-yls) -4- (2- methyl -4- methoxybenzenes amido) quinazoline -6- bases] urea

1- benzoyls -3- [7- (4- methylpiperazine-1-yls) -4- (the chloro- 3- trifluoromethylbenzenes amidos of 4-) quinazoline -6- bases] urea Or

1- benzoyls -3- [6- (morpholine -4- bases) -4- anilinoquinazoline -7- bases] urea；Or the salt of these compounds.

3. a kind of fragrant formyl urea coupling quinazoline compounds shown in formula (I) or its of preparing in claim 1 can pharmaceutically connect The method for the salt received, which is characterized in that it includes having formula (VII) compound represented and formula (VIII) compound represented In solvent, formula (I) compound represented is generated；

Wherein R₇Or R₈One of be NH₂；

R₇Or R₈In another be H ,-O-CH₃、-O-CH₂-CH₃、-O-CH₂(CH₃)₂、

R₁、n₁、R₄、n₂Definition and formula (I) in R₁、n₁、R₄、n₂Definition it is identical.

4. a kind of fragrant formyl urea coupling quinazoline ditosylate salt shown in formula (I) is prepared in claim 1 according to claim 3 Close object or the method for its pharmaceutically acceptable salt, which is characterized in that the organic solvent is selected from acetonitrile or anhydrous tetrahydro furan.

5. a kind of fragrant formyl urea coupling quinazoline ditosylate salt shown in formula (I) is prepared in claim 1 according to claim 3 Close object or the method for its pharmaceutically acceptable salt, which is characterized in that including：Formula (I) compound represented is having with acid or alkali Reaction generates formula (X) compound represented in solvent；

Wherein, M is hydrochloric acid, hydrobromic acid, sulfuric acid, hemisulfic acid, phosphoric acid, amino acid, other carboxylic acids, R₁、n₁、R₂、R₃The same formula of definition (I) R in₁、n₁、R₂、R₃Definition it is identical.

6. a kind of fragrant formyl urea coupling quinazoline ditosylate salt shown in formula (I) is prepared in claim 1 according to claim 5 Close object or the method for its pharmaceutically acceptable salt, which is characterized in that M is hydrochloric acid.

7. a kind of fragrant formyl urea coupling quinazoline ditosylate salt shown in formula (I) is prepared in claim 1 according to claim 5 Close object or the method for its pharmaceutically acceptable salt, which is characterized in that formula (I) compound represented reacts organic with acid or alkali Solvent is absolute ethyl alcohol or dichloromethane.

8. a kind of pharmaceutical composition, including virtue formyl urea coupling quinazoline compounds as claimed in claim 1 or 2 and/or its Pharmaceutically acceptable salt and pharmaceutically acceptable carrier, excipient or diluent.

9. pharmaceutical composition according to claim 8, which is characterized in that described pharmaceutical composition includes other active matters Matter.

10. the fragrant formyl urea coupling quinazoline compounds described in claims 1 or 2 and/or its pharmaceutically acceptable salt Prepare treatment and the use in the drug of protein tyrosine kinase inhibitory activity and/or the relevant disease of tubulin inhibitory activity On the way.

11. the fragrant formyl urea coupling quinazoline compounds or its pharmaceutically acceptable salt described in claims 1 or 2 are being made The standby purposes being related in the drug of the relevant disease of tumour.

12. purposes according to claim 11, which is characterized in that the disease is malignant tumour.

13. purposes according to claim 12, which is characterized in that the malignant tumour is lung cancer；Cancer of pancreas；Phosphorus columnar epithelium Cancer；Medullary carcinoma of thyroid gland；Incidence cancer；Cancer of the esophagus；Gastric cancer；Gynaecology's carcinoma or carcinoma of urinary bladder.

14. purposes according to claim 13, which is characterized in that gynaecology's carcinoma is breast cancer.

15. purposes according to claim 13, which is characterized in that the lung cancer is non-small cell lung cancer.